recent developments in the medicinal chemistry of cannabimimetic indoles, pyrroles and indenes

2005, 12, 1395-1411 1395

Recent Developments in the Medicinal Chemistry of CannabimimeticIndoles, Pyrroles and IndenesJ.W. Huffman* and L.W. Padgett

H. L. Hunter Chemistry Laboratory, Clemson University, Clemson, South Carolina 29634-0973, USAAbstract: During the development of new nonsteroidal anti-inflammatory agents, it was discovered that 1-aminoalkyl-3-aroylindoles have affinity for the cannabinoid brain (CB1) receptor. This has led to thedevelopment of over 100 cannabimimetic aminoalkylindoles, and the development of SAR for these compounds.Later work demonstrated that the aminoalkyl moiety was not necessary, and could be replaced by a four- to six-membered alkyl chain without loss of affinity. Investigation of these indoles led to the discovery of a CB2selective ligand, 3-(1-naphthoyl)-N-propylindole. Subsequent work has provided several additional CB2selective indoles. On the basis of a proposed pharmacophore for the cannabimimetic indoles, a series of pyrrolesand indenes were developed, some of which are potent cannabinoids. SAR for several series of pyrroles havebeen developed. Two groups have described cannabimimetic indenes, which have been employed as rigidmodels for the receptor interactions of cannabimimetic indoles with the CB1 receptor. There is some evidencethat the indoles bind to a somewhat different site on the receptor than traditional cannabinoids, and interactwith the receptor primarily by aromatic stacking.

Keywords: Cannabinoid, aminoalkylindole, pyrrole, indene, receptor, indole.

INTRODUCTION subsequent work from the same group confirmed thatcompounds of this group bind to the cannabinoid brainreceptor, some with quite high affinity [11]. One rigid AAI,WIN-55,212-2 (4), has particularly high affinity for thecannabinoid receptors, and has been employed extensively ina number of investigations into the pharmacology of thisgroup of compounds.

In the years following the elucidation of the structure ofD9-tetrahydrocannabinol (D9-THC, 1), the principalpsychoactive constituent of marijuana (Cannabis sativa L.)[1], a comprehensive set of structure-activity relationships(SAR) based on the partially reduced dibenzopyran structureof THC was developed [2-5]. Subsequently, a group at Pfizerdeveloped a series of very potent non-traditionalcannabinoids [6-9]. These SAR were extended to the Pfizercompounds, which lack the dibenzopyran ring present intraditional cannabinoids, but exhibit typical cannabinoidpharmacology. CP-55,940 (2, DMH = 1,1-dimethylheptyl)is representative of this group of compounds, and is almostcertainly the most well-known of these Pfizer non-traditionalcannabinoids.

H3C NO

N

O

O

H3C N

N

O

O

H3CO

43

O CH3

CH3

OH

H3C

H3C

OH

DMH

OH

HO1 2

Fig. (2). Structures of pravadoline and WIN-55,212-2.A few years later, Huffman et al. found that the

aminoalkyl portion of the molecule could be replaced by analkyl group to provide indole derivatives, such as JWH-007(5), that exhibit typical cannabinoid pharmacology [12]. Itwas also found that the benzene ring of the indole is notessential for either receptor affinity or in vivo effects, andcannabimimetic pyrrole derivatives (6, R = various alkylgroups) were reported by the Clemson group [13]. A detailedpresentation of the SAR, of several of these cannabimimeticindoles and pyrroles was published several years ago [14].Several aminoalkylindenes structurally related to thecannabimimetic AAIs have also been prepared, some ofwhich have high affinity for the cannabinoid receptors [15,16]. In these compounds, the indole nitrogen is replacedwith a carbon atom to give 7 and similar compounds.

Fig. (1). Structures of D9-THC and CP 55,940.In 1991, a group at Sterling Winthrop reported that

pravadoline (3) and related compounds inhibited thecontractions of the electrically stimulated mouse vas deferens(MVD), are antinociceptive in vivo and inhibit adenylatecyclase [10]. These aminoalkylindoles (AAIs) were found tointeract with a G-protein coupled receptor in the brain, and

*Address correspondence to this author at the H. L. Hunter ChemistryLaboratory, Clemson University, Clemson, South Carolina 29634-0973,USA; E-mail: [email protected]

0929-8673/05 $50.00+.00 ' 2005 Bentham Science Publishers Ltd.

1396 Current Medicinal Chemistry, 2005, Vol. 12, No. 12 Huffman and Padgett

N

O

R

H3CN

O

R

N

O5 R = n-C5H11, R' = H8 R = n-C3H7, R' = H9 R = n-C3H7, R' = CH3 6

7

R'

Fig. (3). Structures of cannabimimetic indoles, pyrroles and indenes.

The chemistry and pharmacology of cannabimimeticindoles, including the aminoalkylindoles, and the relatedpyrroles and indenes were reviewed in 1999 [17]. Thepresent review will cover developments in this field from late1998 through mid-2004. The similarities and differences inthe interactions of these compounds and traditionalcannabinoids with cannabinoid receptors will be discussed.Prior to describing the medicinal chemistry andpharmacology of these compounds, a brief introduction tosome of the more common methods employed to evaluatethe pharmacology of cannabinoids will be described.

[29]. This functional assay measures G-protein coupledreceptor activation using [35S]GTP g S binding.

The most common in vivo protocol is a mouse model[21], in which a battery of three or four procedures isemployed. These measure spontaneous activity (SA),antinociception (as tail flick, TF), hypothermia (as decreasein rectal temperature, RT) and catalepsy (as ring immobility,RI). A variety of other procedures have been employed toevaluate in vivo pharmacology, however the mouse model iswidely accepted, and this protocol was used for the majorityof the compounds discussed in this review that wereevaluated in vivo. An extensive review of cannabinoidreceptors and the pertinent bioassays has been publishedrecently [30].

PHARMACOLOGY METHODS

CANNABIMIMETIC INDOLESA cannabinoid receptor in rat brain was first described in

1988 [18]. This G-protein coupled receptor wassubsequently cloned, and the primary structure wasdetermined [19]. A human cannabinoid central nervoussystem receptor has been identified, which is virtuallyidentical (97% homology) to that from the rat [20]. It isgenerally accepted that the overt physiological effects ofcannabinoids are mediated through this receptor [21, 22]. In1993, a second human cannabinoid receptor which shows44% identity to the brain receptor was identified and cloned[23]. The transmembrane portion of this receptor shows 66%identity to the central nervous system receptor. This receptoris found primarily in the immune system [24]. The centralnervous system receptor is designated as the CB1 receptor,and that found principally in the immune system as the CB2receptor. Affinity for the CB1 receptor measures the ability ofthe substrate to displace a potent cannabinoid, usuallytritiated CP-55,940 (2), from its binding site in a membranepreparation as described by Compton et al. [22].Alternatively, the displacement of tritiated WIN-55,212-2 (4)has been employed [11]. Affinity for the CB2 receptor isdetermined by the ability of a ligand to displace CP-55,940(2) from its binding site in transfected cell lines [23, 25, 26]or a mouse spleen membrane preparation [27]. An alternativemethod for the in vitro evaluation of cannabinoid activityemploys the inhibition of electrically evoked contractions ofthe isolated mouse vas deferens (MVD) [28].

Following the observation that pravadoline (3) inhibitedcontractions of the electrically stimulated MVD [10], thegroup at Sterling Winthrop carried out an extensive study ofthe SAR of well over 100 related compounds [11, 31].Subsequently, a series of sterically constrained AAIs wasprepared, and it was found that the most effective compoundin MVD activity was WIN-55,212-2 (4). These analogs werealso evaluated in a binding assay, in which the ability of theligand to displace tritiated 4 from its binding site in a ratbrain membrane preparation was measured. There was apositive correlation between these binding data and theMVD assay, and it was concluded that there were manysimilarities both in vitro and in vivo, between the AAIs andtraditional cannabinoids. Confirmatory evidence that theAAIs and traditional cannabinoids bind to the same receptorwas found by Kuster et al. who determined the affinities ofseveral AAIs for the WIN-55,212-2 binding site [32]. Thesecompounds were also evaluated in the standard behavioralprotocol for cannabinoids, and were found to exhibit typicalcannabinoid pharmacology [33].

The Winthrop group reported well over 100 variouscannabimimetic indoles, all of which belong to the sub-group of aminoalkylindoles [10, 11, 31, 34]. These workersstated that the necessary criteria for CB1 receptor affinityincludes an aroyl group at C-3 of the indole, which, formaximum affinity should be 1-naphthoyl or substituted 1-naphthoyl. However, no SAR for aromatic substituents werepresented [31]. Other polycyclic aromatics at C-3 were lesseffective than naphthalene. A number of substituted 3-benzoylindoles were described, however, they had uniformly

Two functional assays are employed to determine theefficacy of cannabinoid receptor ligands at both CB1 andCB2. One of these measures the agonist induced attenuationof the ability of forskolin to stimulate the production ofcAMP [28]. The other assay measures the ability of acannabinoid receptor ligand to stimulate GTPg S binding

Recent Developments in the Medicinal Chemistry of Cannabimimetic Current Medicinal Chemistry, 2005, Vol. 12, No. 12 1397

N

R

O

R' N

R

O

R'

CH3

N

R

O

R'CH3O

10 R' = H13 R' = CH3

11 R = H14 R' = CH3

12 R = H15 R' = CH3

Fig. (4). Structures of various cannabimimetic indoles. R = C3H7 or C5H11 .

low affinity for the receptor. At C-2 of the indole, a grouplarger than methyl destroyed activity, and a hydrogen at C-2was slightly superior to a methyl group. This group statedthat an aminoethyl group appended to the indole nitrogenwas optimum for cannabinoid activity, and that a cyclicamine, such as morpholine, piperidine or thiomporpholinewas necessary as part of the aminoethyl group. Subsequentto outlining these SAR, the Winthrop group employedCoMFA to develop a pharmacophore for the aminoalkylsubgroup of the cannabimimetic indoles [35]. These authorsconcluded that it was probable that these indole analoguesand classical cannabinoids may partly overlap in theirinteractions with the CB1 receptor, however no specific areasof commonality were suggested.

the aminoalkyl group is not necessary for cannabimimeticactivity, but that an alkyl substituent of four to six carbonatoms on nitrogen is necessary [12, 14, 36]. CB1 receptoraffinity and in vivo potency are maximized with an N-pentylsubstituent. For useful CB2 receptor selectivity, high affinityfor this receptor with minimum affinity for the CB1 receptoris essential. Both JWH-015 and another CB2 selectiveindole, JWH-046, 1-propyl-2-methyl-3-(7-methyl-1-naphthoyl)indole (9), have a propyl substituent on nitrogen,and in the effort to develop CB2 selective compounds,emphasis was placed on preparing N-propyl indoles. Fordeveloping SAR at the CB1 receptor N-pentyl substituentswere employed. In agreement with the Winthrop data, a 2-methyl group slightly attenuates activity relative to anunsubstituted 2-position, and larger substituents lead toinactivity [36]. Various 3-(1-naphthoyl) substituents wereinvestigated and it was found that a 7-methyl substituent haslittle effect on activity, while a 4-methoxy group enhancesaffinity for the CB1 receptor [36]. Larger 4-alkoxyl groupseffectively render the compound inactive. Receptor affinitiesand in vivo potencies of several N-propyl- and N-pentyl-3-(1-naphthoyl)indoles (10), 3-(7-methyl-1-naphthoyl)indoles

In 1996, Showalter et al. reported that JWH-015, 1-propyl-2-methyl-3-(1-naphthoyl)indole (8) has selectiveaffinity for the CB2 receptor [25]. This observation, plusefforts to establish SAR for the cannabimimetic indoles ledHuffman et al. to prepare a number of indole derivatives,some of which are very potent cannabinoids [12, 14, 36].The principal difference between the SAR described by thisgroup and that of the Winthrop workers is the finding that

Table 1. Receptor Affinities (CB1 and CB2) and In Vivo Potency for Cannabimimetic Indoles 1015, WIN-55,212-2 (4) and9-THC (1)

Compound Ki (nM)(CB1)

Ki (nM)(CB2)

ED50SA

mol/kga

TFRT

9-THC (1) 412b 3610 b 0.92 2.7 2.5

WIN-55212-2 (4) 1.90.1 b 0.30.2b 0.25c 0.82c 23.0c

8 (JWH-015) 38372b 145b 18.7 84.7 99.1

10, R = n-Propyl (JWH-072) 105055c 17054e NT NT NT

10, R = n-Pentyl (JWH-018) 9.54.5b 2.92.6b 0.44 ~0.09 1.7

13, R = n-Pentyl (JWH-007) 9.54.5d 2.92.6e 0.70 0.25 4.3

11, R = n-Propyl (JWH-076) 21411f 10646f NT NT NT

14, R = n-Propyl (JWH-046) 34338e 165e No Max No Max No Max

14, R = n-Pentyl (JWH-048) 111e 0.50.1e


N

O

R

R'H3CO N

O

R

C2H5

16 R = C3H7, R' = C4H917 R = C4H9, R' = C5H1118 R = C5H11, R' = C6H13

19 R = C3 H7 to C7H15

Fig. (5). Structures of 2-alkyl cannabimimetic indoles.

(11), 3-(4-methoxy-1-naphthoyl)indoles (12) and thecorresponding 2-methylindoles (13, 14, 15) are presented inTable 1. Data for (D 9-THC, 1) and WIN-55,212-2 are alsoincluded in Table 1.

nM. None of the other compounds in this series have Ki 10,000 455 55

40, R = n-Pentyl (JWH-267) 381 16 7.2 0.14

41, R = n-Pentyl (JWH-268) 1379 193 40 0.6

42, R = n-Propyl (JWH-163) 2358 215 138 12

43, R = n-Propyl (JWH-151) >10,000 30 1.1

42, R = n-Pentyl (JWH-166) 44 10 1.9 0.08

43, R = n-Pentyl (JWH-153) 250 24 11 0.5

44, R = n-Propyl (JWH-165) 204 26 71 8

45, R = n-Propyl (JWH-160) 1568 201 441 110

44, R = n-Pentyl (JWH-164) 6.6 0.7 6.9 0.2

45, R = n-Pentyl (JWH-159) 45 1 10.4 1.4

46, R = n-Propyl (JWH-259) 220 29 74 7

47, R = n-Propyl (JWH-261) 767 105 221 14

46, R = n-Pentyl (JWH-258) 4.6 0.6 10.5 1.3

47, R = n-Pentyl (JWH-260) 29 0.4 25 1.9a Ref. 44.


JWH-120 has very little affinity for the CB1 receptor, it hasexcellent affinity for the CB2 receptor (Ki = 6.1 0.7 nM).This compound is highly selective for the CB2 receptor withgreater than 170-fold selectivity. In the series of indoles witha 4-alkyl substituent (36 and 37, R'' = CH3, C2H5, C3H7,C4H9), the CB1 receptor affinities are uniformly very highwhen the nitrogen substituent is pentyl. The greatest CB1receptor affinity in this group is JWH-210 (1-pentyl-3-(4-ethyl-1-naphthoyl)indole, (36, R = C5H11, R = C2H5)with Ki = 0.46 0.03 nM. The 4-propyl (JWH-182, 36, R= C5H11, R = C3H7) and 4-methyl (JWH-122, 36, R =C5H11, R = CH3) analogs have virtually the same, veryhigh affinity for the CB1 receptor with Ki = 0.65 0.03 nMand Ki = 0.69 0.5 nM, respectively. The N-pentylcompounds with small alkyl groups at C-4 and an indole 2-methyl group have CB1 receptor affinities from 1.3 to 1.5nM. With the exception of the 4-methyl compounds (JWH-120 and JWH-148), the N-propyl compounds in this grouphave relatively high CB1 receptor affinities with Ki = 2670nM. The N-pentyl-3-(4-butyl-1-naphthoyl)indoles (36,JWH-240 and 37, JWH-242, R = C5H11, R = C4H9) havesomewhat less affinity for the CB1 receptor than thecongeners with smaller alkyl substituents. The N-propylanalogs (JWH-239, 36 and JWH-241, 37, R = C3H7, R =C4H9), both have very modest affinity for the CB1 receptorwith Ki = 342 20 nM (36) and Ki = 147 20 nM (37).

methoxy group in other positions of the naphthoyl moiety[37]. In order to gain insight into the effect of methoxygroups at other positions, 1-propyl and 1-pentyl-3-(2-methoxy-1-naphthoyl) (4041), 3-(6-methoxy-1-naphthoyl)(4243) and 3-(7-methoxy-1-naphthoyl)indoles (4445) weresynthesized and their CB1 and CB2 receptor affinities weredetermined [46]. The CB1 and CB2 receptor affinities forindoles 4045 are summarized in Table 3.

None of the 3-(2-methoxy-1-naphthoyl)indoles (4041,JWH-265 to JWH-268) have appreciable affinity for the CB1receptor, with Ki > 380 nM. However, JWH-267 (40, R =C5H11) and JWH-268 (41, R = C5H11) have high affinity forthe CB2 receptor (Ki = 7.2 0.14 nM and Ki = 40 0.6nM, respectively). 1-Pentyl-3-(2-methoxy-1-naphthoyl)indole, JWH-267, is a very highly selectiveligand for the CB2 receptor, with greater than 50-foldselectivity over the CB1 receptor.

Only one of the 3-(6-methoxy-1-naphthoyl)indoles (42-43) has significant affinity for the CB1 receptor. For 1-pentyl-3-(6-methoxy-1-naphthoyl)indole (JWH-166, 42, R =C5H11) K i = 44 10 nM. The other three compounds inthis series, JWH-163 (42, R = C3H7), JWH-151 (43, R =C3H7) and JWH-153 (43, R = C5H11) have Ki > 250 nM.However, all of the compounds in this series have frommodest to very high affinity for the CB2 receptor, and JWH-151 is a highly selective ligand for the receptor, with Ki =30 1.1 nM at CB2 with Ki > 10,000 nM at the CB1receptor. In contrast to the 3-(2-methoxy-1-naphthoyl)- and3-(6-methoxy-1-naphthoyl)indoles, which in general have atbest, very modest affinity for the CB1 receptor, the 1-pentyl-3-(7-methoxy-1-naphthoyl)indoles both have high affinity. 1-Pentyl-3-(7-methoxy-1-naphthoyl)indole (JWH-164, 44, R =C5H11), has Ki = 6.6 0.7 nM, while the 2-methylcongener (JWH-159, 45, R = C5H11), has K i = 45 1 nM.The N-propyl compounds, JWH-165 and JWH-160 (44 and45, R = C3H7) have little affinity for the CB1 receptor withKi > 200 nM.

The CB1 receptor affinities for 7-ethyl analogs 38 and 39(Table 3) are similar to those of the corresponding 7-methylcompounds (11 and 14, Table 1). However, in contrast to 1-propyl-2-methyl-3-(7-methyl-1-naphthoyl)indole (JWH-046,14, R = C3H7), which has high affinity for the CB2 receptor(Ki = 16 5 nM) and modest affinity for the CB1 receptor(Ki = 343 38 nM), the corresponding 7-ethyl analog(JWH-239, 39, R = C3H7) has little affinity for eitherreceptor.

It had been observed previously that a 4-methoxy-1-naphthoyl substituent enhances CB1 receptor affinity, butvirtually nothing was known concerning the effect of a

N

O

R

R'R'' N

O

R

R'

C2H5

N

OCH3

O

R'

R

N

O

R

R'

H3CO

N

O

R

R'

OCH3

N

O

R

R'C2H5O

36 R' = H37 R' = CH3R'' = CH3, C2H5, C3H7 or C4H9

38 R' = H39 R' = CH3

40 R' = H41 R' = CH3

42 R' = H43 R' = CH3

44 R' = H45 R' = CH3

46 R' = H47 R' = CH3

Fig. (11). Structures of cannabimimetic indoles with substituted naphthoyl systems. In all cases R = C3H7 or C5H11 .


In the course of preparing a series of N-alkyl-3-(4-methoxy-1-naphthoyl)indoles (12, R = C3H7 to C7H15), aside reaction occurred which led to the production of thecorresponding 3-(4-alkoxy-1-naphthoyl)-N-alkylindoles (48)via an unusual SNAr reaction [47]. The compounds in thisseries have uniformly poor affinity for the CB1 receptor withKi > 200 nM. Although indoles 48 with 4-alkoxysubstituents of four or more atoms have little affinity for thereceptor, N-pentyl cannabimimetic indoles 36 and 37 withalkyl chains of one to four carbon atoms have uniformallyhigh affinity for the CB1 receptor. In order to probe the effectof a 4-alkoxy substituent larger than methoxy, a series of 3-(4-ethoxy-1-napthoyl)indoles (46 and 47) was prepared andthe CB1 and CB2 receptor affinities were determined (Table3).

the efficacy of these compounds, their ability to stimulateGTP g S binding was determined. The results of thesedeterminations are summarized in Table 4. The stimulationis normalized to that produced by 3 m M CP-55,940 (2), amaximally effective concentration of this standardcannabinoid agonist. In addition to JWH-120, JWH-151 andJWH-267, the [35S]GTP g S binding for JWH-015, 1-propyl-2-methyl-3-(1-naphthoyl)indole (8), the lead compound forthe search for CB2 selective cannabimimetic indoles, wasdetermined, and the data are included in Table 4.

As indicated in Table 4, all four of these compounds arepotent in the [35S]GTP g S assay with EC50 values from 5.1 1.0 nM for JWH-120 (36, R = C3H7, R'' = CH3) to 17.7 1.0 nM for JWH-015 (8). One of these CB2 receptorligands, 1-propyl-2-methyl-3-(6-methoxy-1-naphthoyl)indole, JWH-151 (43, R = C3H7) is highlyefficacious with an Emax of 108.5 13.0% relative to CP-55,940. The other three cannabimimetic indoles, 1-propyl-2-methyl-3-(1-naphthoyl)indole, JWH-015 (8), 1-propyl-3-(4-methyl-1-naphthoyl)indole, JWH-120 (36, R = C3H7, R'' =CH3) and 1-pentyl-3-(2-methoxy-1-naphthoyl)indole, JWH-267 (40, R = C5H11), are partial agonists relative to CP-55,940 with Emax values from 65.7 6.4% (JWH-015) to78.1 10.7% (JWH-120).

N

O

R

RO

48 R = n-propyl to n-heptyl

Fig. (12). Structure of 4-alkoxy-1-naphthoylindoles.

Indoles 46 and 47 have weaker affinities for the CB1receptor than the corresponding methoxy analogs (12 and 15,Table 1). However they follow the usual trend in that the N-propyl indoles (JWH-259, 46, R = C3H7 and JWH-261, 47,R = C3H7) have significantly less affinity for the receptorthan the N-pentyl compounds. Neither N-propyl analog has aCB1 receptor affinity better than 220 nM (JWH-259). 1-Pentyl-3-(4-ethoxy-1-naphthoyl)indole (JWH-258, 46, R =C5H11) has very high affinity for the CB1 receptor with Ki =4.6 0.6 nM, however, this is somewhat less than that forthe 4-methoxy analog (JWH-081, 12, R = C5H11, Ki = 1.2 0.1 nM). The 2-methyl compound (JWH-260, 47, R =C5H11) has Ki = 29 0.4 nM which is considerably lessthan that of the 2-methyl-1-pentyl-3-(4-methoxy-1-naphthoyl)indole (JWH-098, 15, R = C5H11) with Ki = 4.5 0.1 nM.

The 1-pentyl indoles provide several structural criteria forrecognition at the CB1 receptor. As noted previously, CB1receptor affinity is reduced slightly by the presence of amethyl group at the 2-position of the indole. With theexception of the 1-pentyl-3-(2-methoxy-1-naphthoyl)indoles(JWH-267, 40, R = C5H11), JWH-268, (41, R = C5H11)and 1-pentyl-2-methyl-3-(6-methoxy-1-naphthoyl)indole(JWH-153, 43, R = C5H11), all of the compounds in thisseries have Ki < 45 nM, indicative of high affinity for thereceptor. The addition of a methyl (JWH-122, 36, R =C5H11, R = CH3, JWH-149, 37, R = C5H11, R = CH3),ethyl (JWH-210, 36, R = C5H11, R = C2H5, JWH-213,37, R = C5H11, R = C2H5) or propyl (JWH-182, 36, R =C5H11, R = C3H7, JWH-181, 37, R = C5H11, R =C3H7) group at C-4 of the naphthalene leads to aconsiderable increase in CB1 receptor affinity, however, abutyl group at C-4 (JWH-240, 36, R = C5H11, R = C4H9,JWH-242, 37, R = C5H11, R = C4H9) results in a slightdecrease in affinity (Table 3). Neither a 7-methyl-1-naphthoyl(JWH-048, 14, R = C5H11, Table 1) nor a 7-ethyl-1-naphthoyl (JWH-234, JWH-262, 39, R = C5H11, Table 3)substituent has a significant effect on affinity for the CB1receptor

A particularly significant result of this study ofcannabimimetic indoles is the discovery of three new highlyselective ligands for the CB2 receptor [44]. Thesecompounds are 1-propyl-3-(4-methyl-1-naphthoyl)indole,JWH-120 (36, R = C3H7, R'' = CH3), which is 173-foldselective, 1-pentyl-3-(2-methoxy-1-naphthoyl)indole, JWH-267 (40, R = C5H11), 53-fold selective, and 1-propyl-2-methyl-3-(6-methoxy-1-naphthoyl)indole, JWH-151 (43, R= C3H7), which is >333 fold selective. In order to evaluate

In the N-pentyl series, a 2-methoxy-1-naphthoylsubstituent (JWH-267, 40, R = C5H11, JWH-268, 41, R =

Table 4. EC50 and Emax Values (mean SEM) for GTP S Binding of CB2 for Selective Ligands. Assays were carried out in

Human CB2 Receptor-Expressing CHO Cells. Emax Values are Reported as Per Cent Relative to 3 M CP-55,940 (2)

Compound EC50 (nM) Emax (% CP-55940)

8, (JWH-015) 17.7 1.0 65.7 6.4

36, R = C3H7, R'' = CH3 (JWH-120) 5.1 1.6 78.1 10.7

40, R = C5H11 (JWH-267) 4.9 0.8 67.3 2.9

43, R = C3H7 (JWH-151) 12.0 2.9 108.5 13.0


C5H11, Table 3) effectively destroys affinity for the CB1receptor, while a 4-methoxy group (JWH-081, 12, R =C5H11, JWH-098, 15, R = C5H11, Table 1) slightlyincreases affinity relative to the unsubstitued analogs.Replacing the 4-methoxy group with a 4-ethoxy (JWH-258,46, R = C5H11, JWH-260, 47, R = C5H11, Table 3)diminishes CB1 affinity somewhat. A 6-methoxy-1-naphthoyl substituent decreases affinity for the CB1 receptorin the compound unsubstitued at C-2 of the indole nucleus(JWH-166, 42, R = C5H11, Table 3); while the 2-methylanalog (JWH-153, 43, R = C5H11,) has little affinity. Incontrast, the 7-methoxy analogs (JWH-164, 44, R = C5H11,and JWH-159, 45, R = C5H11), have receptor affinitiescomparable to those of the 4-ethoxy compounds (Table 3).

1-Pentyl-3-(4-propyl-1-naphthoyl)indole (36, R = C5H11,R = C3H7) is a very high affinity CB1 receptor ligand (K i =0.65 0.03 nM, Table 3), and it was docked in the sameposition as JWH-018 (10, R = C5H11), JWH-122 (27) andJWH-081 (12, R = C5H11) [44]. These docking studiesshowed that the N-pentyl tail of JWH-182 extends over aphenylalanine on helix-3 of the CB1 receptor, and the indolemoiety is between transmembrane helices 5 and 6. Thenaphthoyl ring is intracellular to a tryptophan on helix-5 andanother on helix-6 , with the 4-propyl substituent on thenaphthyl ring situated in an open area within the bindingpocket. In this position, both the indole and naphthoyl ringshave stacking interactions with the tryptophans, and thecarbonyl oxygen forms a weak hydrogen-bond with thetryptophan on helix-6.In general, cannabimimietic indoles with N-propyl

substituents have significantly less affinity for the CB1receptor than the corresponding N-pentyl compounds.Although a methyl group at C-2 of the indole usuallyattenuates CB1 receptor affinity somewhat, in the case of thecompounds with an unsubstituted naphthoyl group (JWH-015, 8, JWH-072, 10, R = C3H7) and the 4-methyl-1-naphthoyl analogs (JWH-120, 36, R = C3H7, R = CH3and JWH-148, 37, R = C3H7, R = CH3), the 2-methylcompounds have considerably greater CB1 receptor affinitiesthan the unsubstituted compounds (Tables 1 and 3). Thesituation is similar for the 1-propyl-3-(4-butyl-1-naphthoyl)indoles (JWH-239, 36, R = C3H7, R = C4H9and JWH-241, 37, R = C3H7, R = C4H9). However, the 2-methyl analog (JWH-241) has only slightly more than two-fold greater affinity for the CB1 receptor than JWH-239.With the exception of the 4-ethyl- (JWH-211, JWH-212),and 4-propyl-1-naphthoylindoles (JWH-180, JWH-189),none of the N-propyl-3-(4-alkyl-1-naphthoylindoles) has aCB1 receptor affinity of less than 100 nM. In the N-pentylseries, the 4-propyl-1-naphthoylindoles (JWH-182, JWH-181) have exceptionally high affinity for the CB1 receptor,respectively (Table 3). These high affinities are reflected inthe N-propyl analogs; JWH-180 (36, R = C3H7, R =C3H7) has K i = 26 2 nM and JWH-189 (36, R = C3H7)has Ki = 70 0.8 nM. In the methoxynaphthoyl series(Tables 1 and 3), the relative magnitudes of the CB1 receptoraffinities for the N-propyl indoles parallel those of the N-pentyl analogs. However, the compounds in this series havelittle affinity for the CB1 receptor with affinities from 204nM, to >10,000 nM with the exception of JWH-079 (12, R= C3H7), which has K i = 63 3 nM.

Using the docking position employed for JWH-182, theconsequences of substitution at other positions on thenaphthoyl ring were explored. Substitution at the 2-naphthoyl position as in 1-pentyl-3-(2-methoxy-1-naphthoyl)indole (JWH-267, 40, R = C5H11, Table 3)causes a large decrease in affinity, relative to the 4-propyl-1-naphthoyl analog (JWH-182). Docking studies show that the2-methoxy group in JWH-267 has severe steric conflictswith the tryptophan on helix-6, causing the ligand to losemost of its aromatic stacking interactions.

Similar docking studies indicated that varioussubstituents can be placed at C-4 of the naphthoyl moiety,and do not cause a significant decrease in affinity, becausethere is a fairly wide and deep lipophilic binding pocket inthis region of the receptor. However, substitution at C-6results in diminished affinity for 1-pentyl-3-(6-methoxy-1-naphthoyl)indole (JWH-166, 40, R = C5H11, Table 3)relative to the 4-propyl-1-naphthoyl analog (JWH-182, 36,R = C5H11, R = C3H7). In its lowest energy conformation,a methoxy substituent at C-6 has some steric conflicts withtwo amino acids that are alleviated by rotation of themethoxy group out of the plane of the naphthoyl ring into ahigher energy rotameric state. The necessity for the methoxygroup to assume a higher energy conformation in order to beaccommodated at the binding site, may contribute to thereduced CB1 affinity of JWH-166 relative to JWH-182.Substitution at C-7 of the naphthoyl ring results in only aslight reduction in affinity for 1-pentyl-3-(7-methoxy-1-naphthoyl)indole (JWH-164, 44, R = C5H11, Table 3).Docking studies show that a methoxy substituent at C-7encounters no steric problems in its minimum energyconformation. However, the methoxy group blocks thearomatic stacking interaction between the naphthoyl ring andthe tryptophan on helix-5, which is present in the 4-propylanalog. This loss of an aromatic stacking interaction mayaccount for the 10-fold reduction in affinity of the 7-methoxycompound (JWH-164, 44, R = C5H11) relative to the 4-propyl analog (JWH-182, 36, R = C5H11, R = C3H7).

To gain insight into the receptor interactions responsiblefor the SAR of these cannabimimetic indoles at the CB1receptor, molecular modeling and receptor docking studieswere carried out. These studies were similar to thosedescribed above for naphthoylindoles JWH-018 (10, R =C5H11), JWH-122 (27) and JWH-081 (12, R = C5H11) [44].The set of 3-(4-propyl-1-naphthoyl)indoles (JWH-180, 36, R= C3H7, R = C3H7, JWH-189, 37, R = C3H7, R =C3H7, JWH-182, 36, R = C5H11, R = C3H7, JWH-181,37, R = C5H11, R = C3H7 Table 3) and the set of 3-(6-methoxy-1-naphthoyl)indoles (JWH-163, 42, R = C3H7,JWH-151, 43, R = C3H7, JWH-166, 42, R = C5H11, JWH-153, 43, R = C5H11 Table 3) were chosen. In addition, theN-pentyl-3-(2-methoxy-1-naphthoyl)indoles (JWH-267, 40,R = C5H11 and JWH-268, 41, R = C5H11, Table 3) wereexamined.

Based on a study of rigid naphthylidene-substitutedaminoalkylindene analogs of cannabimimetic indoles thatmimic the s-cis or s-trans conformation of thecannabimimetic indoles, it was concluded that that the s-trans conformation is probably the preferred conformation forthe interaction of cannabimimetic indoles at both the CB1and CB2 receptors [16]. For this reason, the lowest energy s-trans conformer of 2-methyl-1-pentyl-3-(4-propyl-1-


N

O

NO2

I

N

CH3

N

O

CH3

N

O

OCH3I

49 50

Fig. (13). Structures of AM1241 and AM630.

naphthoyl)indole (JWH-181, 37, R = C5H11, R = C3H7).),rather than its global minimum energy s-cis conformer wasused in the docking studies. Because of the use of the s-transconformer as the bioactive conformation for the C-2 methylindoles, the affinities of ligands in this series can, in general,be expected to be reduced relative to those of thecorresponding indoles without a C-2 methyl group for whichthe global minimum energy conformers are s-transconformers. Such a general reduction is, in fact, seen in thisseries (Tables 1 and 3).

receptor has 82-fold selectivity for the CB2 receptor [48].This compound has been found to produce antinociceptionto thermal stimuli, an effect which is blocked by the CB2receptor antagonist AM630 (50) [48, 49]. In another study itwas found that the antihyperalgesic and antialloldynic effectsof AM1241 were blocked by the CB2 antagonist SR144528,but not by the CB1 antagonist SR141716 [50]. These dataindicate that these effects are mediated through the CB2receptor. Similar effects were noted in capsaicin inducedhyperalgesia and aalodynia [51].

Compared to their N-pentyl congeners, each analog in theN-propyl series shows reduced CB1 receptor affinity. In theN-pentyl series, the pentyl tail resides in a hydrophobicbinding pocket which appears to orient the aromatic rings ofthe ligand for aromatic stacking interactions with thereceptor. The N-propyl tail is too short to access thishydrophobic pocket and simultaneously allow the ligand toengage in aromatic stacking interactions. As a result, ligandswith the propyl substituent may have more difficulty inassuming the correct aromatic region orientation necessaryfor productive binding at the CB1 receptor. The importanceof an alkyl chain of certain length is very reminiscent of theclassical cannabinoids for which it has been shown that C-3alkyl chains shorter than pentyl have severely reduced CB1affinities [2-5].

Very recently, a group at Bristol-Myers Squibb hasdescribed two new groups of indole based cannabinoids. Oneseries of compounds was comprised of amides derived from asubstituted indole 3-carboxylic acid, several of which showselectivity for the CB2 receptor [52]. The most highlyselective compound in this series is phenylalanine derivedamide 51, which has excellent affinity for the CB2 receptor(Ki = 8 nM) and little affinity for the CB1 receptor (Ki =4000 nM). The second series of cannabimimetic indoles arepyridones, derived from compounds similar to 51 [53]. Oneof these indolopyridones (52) has very high affinity for theCB2 receptor (Ki = 1.0 0.2 nM), and also has high affinityfor the CB1 receptor (Ki = 16 4 nM). In addition,indolopyridone 52 is orally effective in a mouse model ofinflammation.

In addition to the new cannabimimetic indoles reportedby the Clemson group, several other new compounds havebeen described, some of which are very promising, highlyselective ligands for the CB2 receptor. One indole derivative,AM1241, (2-iodo-5-nitrophenyl)-[1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl]methanone (49) with K i = 3.4 0.5nM at the CB2 receptor and Ki = 280 41 nM at the CB1

Two studies of the in vitro metabolism ofcannabimimetic indoles have been carried out by Zhang etal. [54, 55]. Both of these studies employed rat livermicrosomes, and the metabolites were characterized by acombination of mass spectrometry and NMR spectroscopy.In the initial study, WIN-55,212-2 (4) provides two majorand at least six minor metabolites [54]. The major

N

O

CH3

N

O

N

H

CO2CH3

OCH3

N

O

N

O

OCH3

N

CH3CH3

H3C

51 52

Fig. (14). Bristol-Myers Squibb cannabimimetic indoles.


CO2H

CH3

SOCH3

F

N

CO2H

CH3

Cl

H3CO

O

N

HAr

O53 54 55Fig (15). Structures of sulindac, indomethacin, and cannabimimetic indenes.

metabolites are dihydrodiols, derived by arene oxidation ofthe naphthalene ring of 4 [56]. The major metabolites werethe only compounds present in sufficient quantity for NMRstudies, the other metabolites were characterized only bymass spectrometry. The minor products included twomonohydroxy compounds and metabolites derived byoxidation of the morpholine ring. The second study was aninvestigation of the metabolism of AM630 (50), in whichthe metabolites were characterized by mass spectrometry[55]. A total of 17 metabolites were identified, whichincluded cleavage of the methyl ether, aromatichydroxylation and a variety of products resulting fromoxidation of the morpholine ring, with and without ethercleavage.

nM). The CB1 receptor affinities of the corresponding Zisomers are significantly lower.

Careful preparation of the pure E- (7) and Z-isomers of 4-[2-[1-(1-naphthalenylmethylene)-1H-inden-3-yl]ethyl]mor-pholine and 4-[2-[2-methyl-1-(1-naphthalenylmethylene)-1H-inden-3-yl]ethyl]morpholine by Reggio et al. afforded anopportunity to study which stereoisomer was responsible forbiological activity [16]. The compounds described byReggio's group were carefully purified by chromatography,and the structures assigned by 1H NMR techniques,primarily NOE experiments. Molecular modeling studiesdemonstrated that the naphthyl group of WIN-55212-2 andthe p-methoxyphenyl group of pravadoline occupied thesame region of space. Comparison of WIN-55212-2 with theindenes indicated that only a small amount of energy wasrequired to overlay the naphthyl rings of the two classes ofligands. These studies support the appropriateness of usingthese rigid analogs as models for the s-cis and s-transconformers of cannabimimetic indoles. The E isomers werefound to have high affinity for both receptor subtypes,whereas the Z-isomers exhibit poor affinity. Since the E-isomers of the indenes are a model for the s-trans conformerof the indoles, this evidence suggests that s-trans is thebioactive conformation.

R

R1

56-59Fig. (16). Structures of Indenes 56-59.

INDENESStudies involving mutant receptors and molecular

modeling strongly suggest that cannabimimetic indolesinteract with the cannabinoid receptors primarily througharomatic stacking [39, 40, 43]. The importance of aromaticgroup orientation in the indene series supports thishypothesis and implies that the indenes interact with theCB1 receptor through the same mechanism as the indoles[16]. In order to exclude a possible hydrogen-bondingmechanism of these ligands with the receptor, a series ofindenes was prepared with an alkyl group in place of theethylmorpholino found in 7 and 55. [44 and R. Mabon,unpublished work].

Cannabimimetic indenes were first prepared by theSterling-Winthrop group, while studying the effects ofpravadoline (3) on the central nervous system [15]. It wasobserved that sulindac (53), an indene analog ofindomethacin, (54), has anti-inflammatory activitycomparable to that of indomethacin, but lacks the CNS sideeffects of 54. Several 1-(2-(4-morpholino)ethyl)-3-arylidenederivatives were prepared as mixtures of E and Z isomers.Derivatives in which the appended aryl group was asubstituted phenyl ring, exhibited low affinities. Two E-naphthylidene analogs, (55), showed good affinity (Ar = 1-naphthyl, IC50 = 1.0 nM; 4-methoxy-1-naphthyl, IC50 = 0.9

The affinities of several of these compounds as mixturesof E- and Z- isomers for the CB1 receptor were determined

Table 5. Receptor Affinities of Indenes Tested as Mixtures of E and Z Stereoisomers

Compound R R1 Ki (nM) CB1

JWH-171, 56 pentyl H 51 2

JWH-170, 57 propyl H 698 27

JWH-173, 58 pentyl CH3 108 12

JWH-172, 59 propyl CH3 140 8


N

R

O

60-64

NAr

O

65-70

N

R1

R5 R2

O

R3R4

71-84

Fig. (17). Structures of Cannabimimetic Pyrroles.

and are shown in Table 5. The introduction of a pentylgroup (56, JWH-171) afforded a mixture of E and Z isomersthat showed good affinity (Ki = 51 2 nM) for the CB1receptor, however, this is somewhat less than that of indene7. The E-isomer of 56 (35, JWH-176) shows increasedaffinity for the CB1 receptor, with Ki = 26 4 nM. [44] Theintroduction of a propyl group in JWH-170 (57) results insignificantly attenuated CB1 affinity, a trend which has beenseen repeatedly in the indole series. The presence of a 2-methyl substituent results in reduced CB1 affinity for thepentyl compound (58, JWH-173), but increased affinity for

determined that the benzene moiety of the indole was notnecessary for biological activity [13]. Since it appearedpossible that these pyrrole derivates would showcannabimimetic activity, the synthesis of a series of alkylpyrroles (6) analogous to previously prepared indoles wasundertaken. These compounds showed reduced affinityrelative to their indole counterparts, but demonstrated asimilar trend with regard to the N-alkyl chain length, whereCB1 receptor affinity peaks at around five carbons. 3-(1-Naphthoyl)-N-pentylpyrrole is relatively potent in thespontaneous activity and tail flick assays, and causes a dose-

Table 6. Receptor Affinities of 2-Phenyl-4-(1-naphthoyl)-N-alkylpyrroles

Compound R Ki (nM) CB1

JWH-156, 60 propyl 890 364

JWH-150, 61 butyl 59.7 1.0

JWH-145, 62 pentyl 11.6

JWH-147, 63 hexyl 9.4

JWH-146, 64 heptyl 19.0

the propyl compound (59, JWH-172) relative to JWH-171(56).

dependent inhibition of electrically evoked contractions ofthe mouse vas deferens that could be antagonized bySR141716 [13, 57].

PYRROLES Based upon the hypothesis that cannabimimetic indoles,and thus the corresponding pyrroles, interact with thereceptor largely through aromatic stacking, a series of 2-phenyl-4-(1-naphthoyl)-Nalkyl pyrroles (60-64) wassynthesized. With the exception of the N-propyl derivative(JWH-156, 60), these compounds exhibited good affinity for

Based on the alignment proposed by Huffman et al.[12],in which the ketonic carbonyl of WIN-55212-2 (4) and thephenolic hydroxyl of THC (1) are overlaid, as are thenaphthalene moiety of 4 and the A-ring of 1, it was

Table 7. Receptor Affinities 2-Aryl-4-(1-naphthoyl)-N-pentyl pyrroles, 65-70

Compound Aryl Ki (nM) CB1

JWH-309, 65 1-naphthyl 40.83 3.32

JWH-347, 66 2-naphthyl 333.7 17.0

JWH-243, 67 p-methoxyphenyl 285 40.3

JWH-292, 68 o-methoxyphenyl 29 0.7

JWH-308, 69 p-fluorophenyl 41 1.4

JWH-307, 70 o-fluorophenyl 7.7 1.8


Table 8. CB1 and CB2 Affinities of pyrroles 71-84

Compound R1 R2 R3 R4 R5 Affinity Ki (nM)

rCB1 hCB2

71 C5H11 H 1-naphthyl H H 30.5 4.7 552 314

72 C5H11 CH3 1-naphthyl H CH3 45.3 7.5 9.85 2.1

73 C3H7 CH3 1-naphthyl H CH3 >1000 309.7 20.8

74 pClC6H4CH2 CH3 1-naphthyl H CH3 83.7 17.8 55.6 26.5

75 C5H11 CH3 1-naphthyl Br CH3 13.3 0.5 6.8 1.0

76 C3H7 CH3 1-naphthyl Br CH3 780 326 691.3 101.3

77 pClC6H4CH2 CH3 1-naphthyl Br CH3 38 7.2 194.5 27.5

78 C5H11 H 1-naphthyl (CH2)4 235.8 6.2 139 55

79 C5H11 CH3 C6H5 H CH3 >1000 >1000

80 C5H11 CH3 C6H5 Br CH3 >1000 >1000

81 pClC6H4CH2 CH3 C6H5 H CH3 >1000 >1000

82 C5H11 CH3 HO(CH2)3 H CH3 >3000 >10000

83 C5H11 CH3 o(CH3CO)C6H4NH H CH3 367.3 31.2 >1000

84 C5H11 CH3 c-C6H11 NH H CH3 415.5 79.5 483.5 211

the CB1 receptor (Table 6). Retaining the pentyl group,several analogs of JWH-145 (62) with substituted phenylsubstituents (65-70) have been prepared, and their receptoraffinities have been determined (Table 7). These compoundsexhibit a range of affinities for the CB1 receptor, with somecompounds exhibiting affinities similar to that of 62, andothers displaying little or no affinity. Initial results indicatethat para-substituents provide decreased receptor affinitywhen compared with 62. This appears to be the case,regardless of the electronic nature of the substituent, althoughthere is not enough evidence to rule out electronic effects.Increase in substituent size from fluoro to methoxy results ina rapid decline of affinity. In both the ortho and parapositions, higher receptor affinity is provided by the smallerfluoro substituent with the difference more pronounced in thepara position. This trend is observed with 2-(1-naphthyl)and 2-(2-naphthyl)pyrrole substituents. The 2-naphthylsubstituent has one ring oriented such that it is equivalent toa meta and para substituent on the aryl ring attached tothe pyrrole. Thus, the 2-naphthyl compound, (66), has asignificantly lower affinity for the CB1 receptor than thepyrrole with a 1-naphthyl substituent at C-2, (61).

These compounds also show little affinity for either receptor,although their affinities are somewhat enhanced relative topyrroles 79-81. Replacement of the C-3 aromatic systemwith a 3-hydroxypropane (82) in an attempt to mimic thenorthern aliphatic hydroxyl of some successful traditionalcannabinoids results in a complete loss of affinity [58].Substitution of both a -positions of the pyrrole with methylgroups has little effect on affinity for either receptor, and theintroduction of a bromine atom to the unsubstituted b -position results in a slight increase in binding for bothreceptor subtypes. The addition of a cyclohexyl ring (78)connecting the 4- and 5-positions greatly reduces affinity,although it is assumed that the substituent occupies thesame location as the benzenoid moiety of the correspondingindoles.

CONCLUSION

Modeling studies of the receptor and results obtainedwith mutant CB1 receptors strongly suggest thatcannabimimetic indoles, and presumably the pyrroles andindenes, interact at a different site in the receptor thantraditional cannabinoids and endogenous cannabinoids, suchas anandamide. These studies also indicate that these classesof cannabinoid receptor ligands interact with the CB1, andprobably the CB2 receptor, primarily by aromatic stackinginteractions. These interactions with the CB1 receptor areconsiderably different than those of the traditionalcannabinoids, and it now appears unlikely that it will bepossible to develop a universal pharmacophore for thecannabimimetic indoles and the traditional cannabinoids.The experiments with mutant CB1 receptors combined withmodeling studies have shed considerable light on the natureof the interactions of various classes of cannabinoids with the

Due to the relatively high affinity displayed by the hybridcannabinoid JWH-161 (20) [42] pyrrole derivatives withother substituents appended to the pyrrole nucleus have beensynthesized [58]. Replacement of the naphthoyl ring systemresulted in decreased affinity for the CB1 and CB2 receptors,shown in Table 8. The presence of a benzoyl substituent atC-3 gives compounds 79-81, which have no appreciableaffinity for either the CB1 or CB2 receptor. Two compounds,83 and 84, with carboxamido groups at C-3, were alsoprepared. It was predicted that the carboxamido group wouldoccupy the same spatial location as the naphthyl ring of thecannabimimetic indoles or the cyclohexene ring of D

8-THC.


CB1 receptor, and in the future should assist in providing afirm basis for the continued development of the SAR of bothclassical and indole based cannabinoids.

[10] Bell, M. R.; D'Ambra, T. E.; Kumar, V.; Eissanstat, M. A.;Herrmann, J. L.; Wetzel, J. R.; Rosi, D.; Philion, R. E.; Daum, S. J.;Hlasta, D. J.; Kullnig, R. K.; Ackerman, J. H.; Haubrich, D. R.;Luttinger, D. A.; Baizman, E. R.; Miller, M. S.; Ward, S. J. J. Med.Chem. 1991, 34, 1099.Although much has been accomplished in developing the

medicinal chemistry of the cannabimimetic indoles, pyrrolesand indenes in the nearly 15 years that the biological activityof these compounds has been recognized, a great dealremains to be done. Inter alia, these include further study ofthe SAR of the indenes and pyrroles, which should shedadditional light upon the detailed interactions of theseligands with the cannabinoid receptors. Also, thedevelopment of additional ligands which are highly specificfor each receptor should be carried out in order to developfurther insight into the physiological role of each receptor,and with the ultimate goal of developing clinically usefulcompounds. In the past few years, the significance of theCB2 receptor has become apparent, and it will be necessaryto identify additional ligands that show a high degree ofaffinity for CB2 relative to CB1. The in vivo pharmacologyof such selective agonists should be informative in terms ofultimately identifying the role of endogenous cannabinoidsin animal physiology. Finally, although a great deal of workhas been carried out concerning the SAR of thecannabimimetic indoles, additional systematic studies of theeffects of various substituents on the indole nitrogen and ringcarbons, as well as on the naphthalene ring need to be carriedout.

[11] D'Ambra, T. E.; Estep, K. G.; Bell, M. R.; Eissenstat, M. A.; Josef,K. A.; Ward, J.; Haycock, D. A.; Baizman, E. R.; Casiano, F. M.;Beglin, N. C.; Chippari, S. M.; Grego, J. D.; Kullnig, R. K.; Daley,G. T. J. Med. Chem. 1992, 35, 124.

[12] Huffman, J. W.; Dai, D.; Martin, B. R.; Martin, B. R.; Compton, D.R. Bioorg. Med. Chem. Lett. 1994, 4, 563.

[13] Lainton, J. A. H.; Huffman, J. W.; Martin, B. R.; Compton, D. R.Tetrahedron Lett. 1995, 36, 1401.

[14] Wiley, J. L.; Compton, D. R.; Dai, D.; Lainton, J. A. H.; Phillips,M.; Huffman, J. W.; Martin, B. R. J. Pharmacol. Exp. Ther. 1998,285, 995.

[15] Kumar, V.; Alexander, M. D.; Bell, M. R; Eissenstat, M. A.;Casiano, F. M.; Chippari, S. M.; Haycock, D. A.; Luttinger, D. A.;Kuster, J. E.; Miller, M. S.; Stevenson, J. I.; Ward, S. J. Bioorg.Med. Chem. Lett. 1995, 5, 381.

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Howlett, A. C. Mol. Pharmacol. 1988, 34, 605.[19] Matsuda, L. A.; Lolait, S. J.; Brownstein, M. J.; Young, A. C.;

Bonner, T. H. Nature 1990, 346, 561.[20] Grard, C. M.; Mollereau, C.; Vassart. G.; Parmentier, M.

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B. R. J. Pharmacol. Exp. Ther. 1988, 247, 1046.[22] Compton, D. R.; Rice, K. C.; De Costa, B. R.; Razdan, R. K.;

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ACKNOWLEDGEMENTS [23] Munro, S.; Thomas. K. L.; Abu-Shar, M. Nature 1993, 365, 61.[24] Pertwee, R. G. Pharmacol. Ther. 1997, 74, 129.

The author thanks Dr. Patricia H. Reggio of theUniversity of North Carolina at Greensboro for many helpfuldiscussions over a several year period. The work carried outat Clemson University which is included in the review wassupported by grants DA03590 and DA15340 to JWH andDA15579 to LWP, all from the National Institute on DrugAbuse. The author also thanks Drs. Billy R. Martin, JennyL. Wiley, David R. Compton, Dana E. Selley and Mary E.Abood of Virginia Commonwealth University for thepharmacological evaluation of the compounds prepared inour laboratory. Thanks is also extended to the graduatestudents and postdoctorals at Clemson University whocarried out the work from our group described in this review.

[25] Showalter, V. M.; Compton, D. R.; Martin, B. R.; Abood, M. E. J.Pharmacol. Exp. Ther. 1996, 278, 989

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