serotonin receptor affinities of psychoactive phenalkylamine analogues

8/6/2019 Serotonin Receptor Affinities of Psychoactive Phenalkylamine Analogues

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294 J . M e d . C h e m .quantum yield in the presence of transfer. $Do was measured withthe corresponding [Phe4]enkep halin nalogues. In the compu-tation of Rot a value of 2/ 3 was used for 2 on the basis of argum entswhich have recently been outlined in detail.14 For the T yr-Tr pdonor-accep tor pair a value of Jm = 4.8 X M- cm6 wasa do pt ed from t he l i t e r a t ~ r e , ~ ~hile in the case of the Tyr-(40) J. Eisinger, B. Feuer, and A. A. Lamola, Biochemistry,8, 3908(1969).

1980, 23 , 294-299(0Me)-Trp pair a performed computation based on the correctedfluorescence emission spe ctrum of [Tyr(OMe),Met]enkephalinand t he absorption spectrum of tryptophan resulted in a valueof 9.1 XAcknowledgment. This work was supported by anoperatin g gran t of the M edical Researc h Council of C anada(MA-5655). The excellent technical assistance of U. G.Goehlert,T. M. D. Nguyen, and C. Lemieux is gratefullyacknowledged.

M-I cm6 for th e ove rlap integral.

Serotonin Receptor Affinities of Psychoactive Phenalkylamine AnaloguesRichard A. Glennon,* Step hen M. Liebowitz, and G eorge M. Anderson I11D e p a r t m e n t of Ph a r ma c e u t i c a l C h e mi s t r y , S c h o ol of Pharm acy , Medical College o f Vi rgin ia , Vi rgin ia Com mon wea l thUn i v e r s i t y , R i c h mo n d , V i r g in i a 23298. Re c e iv e d S e p t e mb e r 5 , 1979

Employing a r at fu ndus model, the serotonin (5-H T) receptor affinities of 45 phenalkylamine analogues weredeter mine d. Phen ethyla mine a nd phenylisopro pylamine possess relatively low receptor affinities; in general, mono-,di-, and trim ethoxylation enha nce affinity. Of the dis ubstitu ted comp ounds, methoxyl groups a t the 2 and 5 positionsare optim al for imp artin g a high affinity. 4-Methylation, 4-ethylation and 4-bromination also enhance receptoraffinity, while N,N-dimethylation of the termina l amine decreases affinity. a-Methylation of phenethylam ines haslittle effect on affinity when racemates are examined. Introduction of a benzylic keto group can either increaseor decrease affinity, depending upon the presence of other arom atic substitue nts. Th e most behaviorally activecompounds were found to possess t he highest 5 -H T receptor affinities, while less active compounds were found topossess lower affinities.

The involvement of serotonergicsystems may play a rolein the mechanism of action of various hallucinogenic/psychotomimetic agen ts such as LSD an d derivatives oftryptam ine and phenalkylamine. Suggestionsto this effectare suppo rted by m icroiontophoretic studies, brain hom-ogenate binding assays, and various biochemical investi-gations; much of this evidence has been reviewed byBrimblecombe and Pinder and, more recent ly, byFreedm an.2 Other neurotransm itter systems, e.g., dopa-minergic, might also be involved, to varying degrees, in themechanism of action of these agent^;^^^ however, there isa need to investigate the serotonergic component of th esemechanisms in greater detail. Vane initially reported th atseveral phenethylamine and phenylisopropylamine ana-logues interact in an agonistic manner with 5-H T receptorsof the rat stomach fund us preparation an d other investi-gators have since examined the agonistic effects of anumber of such compounds using a variety of isolatedtissue preparation^.^ In a recent publication from thislaboratory, we reported that the more potent hallucino-genic tryptamine and phenalkylamine analogues possessa relatively high affinity for the 5-HT receptors of theisolated rat fund us preparatio n w hile the less behaviorallyactive derivatives possess a lower affinity.6 In a subse-qu en t publication, we reported th e results of a more ex-tensive SA R investigation of a series of try pta mi ne ana-

R. W. Brimblecombe and R. M. Pinder, HallucinogenicAgents, Wright-Scientechnica, 1975.D. X. Freedman and A. E. Halaris in Psychopharmacology:A Generation of Progress, M. A. Lipton, A. Dimascio, and K.F. Killam, Eds., Raven Press, New York, 1978, pp 347-359.P. M. Whitaker and P. Seeman, J . Pharm. Pharmacol.,29,506(1977).P. C. Waldmeier and L. Maitre, Psychopharmacology, 52, 137(1977).J. R. Vane in Adrenergic Mechanisms, J. R. Vane, G. E. W.W ols ten hoh e, and M. OConnor, Eds., Little, Brown and Co.,Boston, 1960, pp 356-372.R. A. Glennon, S. M. Liebowitz, and E. C. Mack, J . M e d .C h e n . , 21, 822 (1978).

10gues.~ We now delineate th e results of a detailed ex-amination of the 5-HT receptor affinities of a series ofphenalkylamine analogues.Chemistry. While biological da ta have been previouslyreported for the 2,4-dimethoxy compound 16, no meltingpoint or microanalytical da ta could be found in th e liter-ature. Compound 16 was prepared by the catalytic hy-drogenation of the 2-aminopropiophenone 43 to a diaste-reomeric mixture of 2-aminopropanols 43a; continued re-duction of th e latte r in th e presence of H C104 gave thedesired produ ct. Alternatively , conden sation of 2,4-di-methoxybenzaldehyde (16a) with Et N 02 afforded thenitropropene 16b, which could be reduced to 16 withLiA1H4.Elbs persulfate oxidation of 2-hydroxy-3-methoxy-benzaldehyde, followed by methylation of the res ulta nthydroquinone, gave 2,3,54rimethoxybenzaldehyde.T h ealdehyde was condensed with E tN 02 and the nitropropenereduced with LiAlH4 o yield the desired 2,3,5-trimethoxycompound 28.Compound 33 was prepared in a ma nner similar to t ha trepo rted by Shulg in,8 i.e., LiA1H4 reduction of 1-(3 ,4,5-trimethoxyphenyl)-2-nitropropene33a). How ever, in anini t ial at tempt to prepare 33a, a benzene solution of3,4,5-trimethoxybenzaldehyde as allowed to react withE tN 0 2 and NH 40A c under refluxing condit ions; in ad-dition to 33a, a white crystalline product, 33b, was isolated.Compound 33b was assigned th e following struct ure basedon NMR, 13C NM R, and mass spectra. Additional suppo rtfor the presence of an im ino group is derived from th eacid-catalyzed hydrolysis of 33b to t he parent 3,4,5-tri -methoxybenzaldehyde and th e corresponding amine 33c.I t is speculated that the desired nitropropene 33a wasformed and then underwent M ichael attack to yield 33b.A survey of the literature reveals that a similar reaction

(7 ) R. A. Glennon and P. K. Gessner, J . M e d . Chem. , 22, 428(1979).(8 ) A. T. Shulgin, J . M e d . Chern., 9, 445 (1966).0022-2623/80/1823-0294$01.00/0 0 980American Chemical Society


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Re c e p t o r A f f i n i t i e s o f Ph e n a l k y l a mi n e An a l o g u e s

IGCH333b

CH3O O C H 3 OCH33

33con a closely related compound has been reported onceb e f ~ r e . ~Th e positional isomer of DOM (37), i.e., 35 , was alsoprepared from the app ropriate aldehyde, via the ni t ro-propene intermediate 35g. Th e aldehyde itself was syn-thesized by catalyt ic reduct ion of 2,6-bis(hydroxy-methyl)-4-methoxyphenol (35a) to the hydroxymethylanalogue 35b, followed by m ethylation and oxidation ofth e resu l tant benzyl alcohol , 35d, with pyridinium chlo-rochromate. Crude 35b an d 35d were prepared accordingto lite ratu re procedures;1 however, heating the crud e 35bin a subl imation apparatus, t o remove as much 2,6-di-methyl-1-hydroxy-4-methoxybenzene35c) as possible,slightly enhances yield (from 45.5 to 60 %) and improvesthe isolation procedure of 35d. Even w ith this, not all oft h e 35c was removed, as evidenced by isolation of 1,4-dimethoxy-2,6-dimethylbenzene3% ) after the methyla-tion step. Compound 36, a position al isomer of DO B (39),was obtained from th e nitropropene 36c. Redu ction of 36cw ith L M H 4gave a mix ture of the desired prod uct 36 an dan equal amou nt of the dehalogenated product 18 , as de-termin ed by GC /MS . Use of AlH3 in place of LiAlH4obviates this problem.Mo st of the remainin g compoun ds have been previouslyreported; these were either p repared via literatu re proce-dures or were, in several instances, obtained from theNational Inst i tu te on Drug Abuse.Results a n d DiscussionSerotonin (&hydroxytryptamine,5-H T) receptor affinityda ta were obtained by treating compounds 1-45 as partialagonists, Le., as mixed agonist-antagonists. These da taare repor ted as apparent pA 2 values in Tables I and 11.Antagonism appears to be competi t ive (except for com-pound 44), as noted by parallel dose-response curves inth e absence and in t he presence of increasing concentra-tions of compound; in addition, Schild plots result innegative slopes approximating unity.In general, there does not app ear to be any simple andstraightforward SAR which would explain the affinitiesof all th e compo unds examined. In some instances, trend scan be observed, while in others the results are con-founding. For example, terminal amine methylat ion, 4-methylation , and a-meth ylation have a predictable effecton affinity. As we have previously repor ted, N,N-di-(9) A.T. hulgin, Erper ient ia , 19,127 (1963).(10) D. .Nichols, C. F. Barfnecht, J. P. Long, R. T. Standridge,H. G. Howell, R. A. Partyka, and D. C. Dyer, J . Med. Chem. ,17,161 (1974).

Journal o f Medic inal Chemis t ry , 1980, Vol. 23 , No. 3 295methylation of the terminal am ine group halves affinity;6for the one compound examined (com paring 32 with 34),N-m ethy lation also halves affinity. 4-M ethylation of th earomatic nucleus, on the other ha nd, doubles affmity. Thisis observed for the methy lation of p henethy lamine (1) itselfan d for the meth ylation of the 2,5-dimethoxy comp ound18 to give 14 and 37 , respectively. Replacement of the4-methyl group of th is lat ter compound with a n ethylgroup, to give DOEt (38), has no addition al effect on af-finity. When racemates are examined, a-methylation hasno appare nt effect on affinity." In eight of the nine casesexamined, the phenethylamine analogue has a n affinitysimilar to its phenylisopropylamine counterpart; comparethe affinities of the following pairs of compounds: 1, 2;5, 6; 7, 8; 9, 10; 17, 18; 19, 20; 22,2 3; 32, 33. In one case,a-methy lation of the methylenedioxy compoun d24 resultsin a slightly enhanced affmity. With respect to the affinityof individual isomers of th e a-m eth yla ted derivatives, th e(I+(-) enantiomers of DOB (391, DOM (37), and MDA(25) constitute the eutomeric series." Th ere is, however,very little difference between the affinity of t he individualisomers of co mpo unds whose racemates possess relativelylow affinities; for examp le, compare 3 with 4 and 11 with12. With few exceptions, mono-, di-, and trimethox ylationof phenethylamine and phenylisopropylamine esult in anincreased 5-H T receptor affinity. In considering mono-methoxy compounds, both 2- and 3-methoxylation enhanceaffinity, while 4-methoxylation has n o sign ificant effect.With respect to dim ethoxy compounds, the pA 2 valuesusually fall within th e 5.4 to 5.6 range with two exceptions;th e affinity of th e 2,6-dimethoxy analogue21 is somewhatlower an d t he affinity of the 2,5-dimethoxy analogues 17an d 18 are an order of mag nitude greater th an tho se of th eother dimethoxy compounds. Other than 17 a nd 18 , al lof the dim ethoxy compo unds possess a lower affmity thanth e 3-methoxy analogues 7 and 8. It should be borne inmind, al though there is no evidence to su pport th is sug-gestion, tha t t he 3-methoxy derivatives may interact withthe 5 -HT receptors either as the 3-methoxy compound, astheir rotamer, the 5-methoxy compound, or perhaps asboth.Th e manner in which these methoxy substitu ents alteraffinity is complex and does not readily lend itself to S A Rinterpretation; this is quite apparen t when th e trimethoxyanalogues are scrutinized. For exam ple, introd uction ofa 4-methoxy group to either the 2,5-dimethoxy comp ound ,18, or the 3,5-dimethoxycompound, 26, to give 29 and 33,respectively, has very little effect on affinity as does 4-metho xylation of pheny lisopropy lamine itself. H owev er,4-methoxylation of 15 to give the 2,3,4-trimethoxy com-pound 27 decreases affinity, while, in contr ast, 4-m eth-oxylation of th e 2,6-dimethoxy compound 21 , to give 31 ,results in a respectable increase in affinity. It may not beth e actu al position of th e meth oxy groups, Le., orien tationabout the periphery of the ring, which is important butrather the subt le effects these subst i tuen ts may have onthe overall electronic constitution of th e arom atic nucleus.Recent studies of various methoxy -substituted aromaticshave demon strated the complexity inherent in the physicalproperties of these seemingly simple molecules. For ex-ample, of th e three isomeric dimethoxybenzenes, th emethoxy groups in both th e para- and m eta-subst i tutedcompounds are planar; by contrast , the preferred orien-tation in o-dimethoxybenzene is nonplanar.12 Thes econform ational preferences result in num erous differences(11)R. .Glennon, Life Sci., 24,1487 (1979).(12) G. M. nderson, P. A. Kollman, L. N. Domelsmith, and K. N.Houk, J . A m . Chem. SOC., 01, 2344 (1979).


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Re c e p t o r A f f i n i t i e s of Ph e n a l k y l a mi n e An a l o g u e sT able 11.Phenalkylamine Analogues5-HT Receptor Affini t ies of Related

X R R D A P nf4 0 b (t) C = O H CH, 5.55 (k0.29 ) 541 (S) - ( - ) C = O H CH, 5.52 (k0.38) 44 2 b ( * ) C = O 4-OMe C H , 5 . 6 5 ( + 0 . 0 7 ) 34 3 b (i ) C =O 2,4-(OMe), CH, 4.95 ( k O . 0 9 ) 34 5 e CH,CH, H H 4.9 3 (*0.09 ) 3a PA, value fol lowed by s tand ard devia t ion.D r. J. D. Smith , MCV/VCU. i f t f rom United Nat ionsNarcot ics Laboratory via Dr. E. May. Unable to deter-mine PA, value; see tex t fo r explanat ion. e HC1 salt pre-pared fro m freshly dis t i l led, commercia l ly available am ine;m p 214-216 C, l i t . ( ref 40) 2 1 8 C. f Number o f -de te r-mina t ions . Comp ounds 40 and 41 p roduce an agon i st i cresponse , a t the higher concen tra t ions tes ted, which ma yhave an e f fec t on th e ac tual PA, value .

or (+)-norpseudoephedrine, 441, are co nst itue nts of th eintox icant khat.13 Introdu ction of a keto group at thebenzylic carbon of amp hetam ine (2 ) serves to doub le af-finity when racemates are compared; however, the sameeffect is observed for the (ST(-)somer 41, as comparedto (8)-( +)-am phe tam ine 4). Th e presence of a methoxygroup at the 2 position of th e arom atic ring appears to havea detrimental effect upon the affinity of 43. [Althoughdiastereomeric mixtures were employed, this 2-methoxygroup also reduces the affinity of th e corresponding 2-amino-l-propanols. For example, the pA2 values for 1-(4-methoxyphenyl)-2-aminopropanol,.22 f 0.12, n = 3,a n d l-(4-methylphenyl)-2-aminopropanol,.40 f .18, n= 4, o not differ sub stantially from those of 10 and 14,while t he pA2 value for 1-(2,4-dimethoxyphenyl-2-amino-propanol (43a), 4.90f .10, n = 3, is considerably lowertha n t he pA z of th e corresponding 2,4-dimethoxyphenyl-isopropylam ine (16).] Perha ps the 2-methoxy subs tituentinterferes w ith a side-chain conform ation which is optimalfor a 5-HT receptor interaction.Compound 44 has an adverse effect on the musclepreparatio n, which precludes the determ ination of a re-liable PA, value. Th e responsiveness of the fund us stripsto 5-HT decreased as the concentration of 44 was in-creased. Th e antagonism produced by 44 may be of anoncom petitive natur e or else 44 is having an effect on th efund us preparation other than its direct effect on the 5 -HTreceptors. Th is problem is being further studie d.A question w hich now em erges is whether or no t a re-lations hip exists between th e 5- HT receptor affinity of th ecompounds investigated and their psychotomimetic ac-tivity in man. W ithin a given series of com pou nds a directrelationship of this s ort may no t exist because the in vitrofundus assay ignores such features as lipid solubility,relative rate of metab olism , distribution , etc., which migh tbe of param ount interest in vivo. Because the primaryimpact of an a-methy l group may be to hinder the rate ofme ta bo l ism of t he ph e na l ky l a m i ne ~ , ~ ~henethylaminesbeing on th e average at least 2-10 times less active thantheir corresponding phenylisopropylamine counterpartsin hu ma n studies,15 h e following discussion willbe limited

44 ( + ) CHOH H CH, d 3Gift from

(13) The Botany and Chemistry of Kh at, United Nations Docu-ment MNAR/3, 1979.(14) A. T. Shulgin in T he Psychopharmacology of Hallucinogens,R. C. Stillman and R. E. Willette, Eds., Pergamon Press, NewYork, 1978, p 74.

J o u r n a l of M e d i c i n a l Ch e mi s t r y , 1980, Vol. 23, N o . 3 297only to analogues of the lat ter series. Phenylisopropy l-amines with pAz values greater than 7.0 usually displaytheir psychotom imetic effect16 at total doses well below 1 0mg: DOB (39), DOE t (38), and DOM (37). Compoundswith pA2values between 6.0 and 7.0 usually possess activityin th e 10-100-mg range: 2,4,5-TMA (29),2,5-DMA (18),MM DA-2 (30), 2,4,6-TMA (31), MDA (25); compou ndswith pA z values below 6.0 are usually less active: 3,4,5-TMA (33) and 3,4-DMA (23).Th e activity of PM A (10) and am phetamine (2) in hu-mans is no t consistent with th e above generalization; bothpossess pA 2values of less than 6.0, yet both are relativelyactive. Amp hetamine produces behavioral effects in bothhuman and nonhuman species which are qualitativelydissimilar to those produced by certain other members ofth e phenylisopropylamine series, such as DOM (37), andis not usually considered to be hallucinogenic. PMA (10)has been reported to possess a pharmacological profilequite similar to that of amphetamine.18Jg Previous in-vestigations (for example, see ref 19-21) have co ncludedthat methoxylated phenylisopropylamines can produceeffects which are both am phetamine-like and LSD-like;the phenylisopropylaminesmay rep resen t a series of com-pounds, then, whose act ivi ty varies on an amphet-amine-like to serotonergic continuum. Th e results ofthis present investigation sup port these previous studiesand suggest, from an affinity standpo int, that compoundssuch as DOB (391, DO Et (38), and DOM (37) may b enearer to th e serotonergic extreme of this conti nuu m (i.e.,have more of a serotonergic comp onen t), while PMA (10)is representative of th e other extrem e.With respect to the affinity of phenalky lamineanaloguesfor the 5-H T receptors of the isolated rat fu ndus prep a-ration, th e results may be summarized as follows: (a)phenethylam ine and phenylisopropylamine possess rela-tively low affinities; (b) extension of the side chain ofphenethylamine by one methylene group, to give thephenylpropylamine 45, further decreases affinity; (c)mono-, di-, and trimethoxy lation generally enhance affin-ity; (d) of th e disu bstituted compounds, a 2,5-dimethoxypattern appears to be optimal; (e) substitutio n of a meth yl,ethyl, or bromo group at t he 4 osition enh ances affinity;(0 a benzylic keto group can either increase or decreaseaffinity, depending upon the presence of oth er ring sub-stituents; (g) N,N-dimethy lation of phen alkylamines re-duces affinity; (h) the presence of an a-methyl group(comparingphenethylamines with phenylisopropylamines)has little effect on affinity when racemates ar e examined;(i) when optically active ph enylisopropylam ines are ex-

V. Braun, G. Braun ,P. Jacob, D. E.Nichols, and A. T. Shulginin Quantitative Structure Activity Relationships of Analges-ics, Narcotic Antagonists, and Hallucinogens, G. Barnett, M.Trsic, and R. E. Willette, Eds., US. Government PrintingOffice, Washington, D.C., 1978, p 27.A. T. Shulgin, Handb. Psychopharmacol., 2, 243 (1978).P. Brawley and J. C. Duffield, Pharmacol. Rev., 24,3 1 (1972);J. C. Winter, Psychophurmocology, 44,29 (1975); H. A. Tilson,T. G. Baker, and J. A. Gylys, ibid., 44, 225 (1975);P. B. Sil-verman and B. T. Ho in Stim ulus Prop erties of Drugs: TenYears of Progress, F. C. Colpaert and J. A. Rosecrans, Eds.,Elsevier/N orth Ho lland Biomedical Press, Amsterdam, 1978,p 189.R. A. Harris, D. Snell, and H. H. Loh, J . Pharmacol . Exp .Ther. , 204, 103 (1978).W. R. Martin, D. B. Vaupel, J.W. Sloan,J. A. Bell, M. Nozaki,and L. D. Bright in ref 14, p 118.F. A. B. Aldous, B. C. Barrass, K. Brew ster, D. A. Buxton, D.M. Green, R. M. Pin der, P. Rich, M. Skeels, and K. J. Tutt ,J . Med. Chem. , 17 , 1100 1974).H. H. Loh and L. F. Tseng in ref 14, p 13.


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298 Journal of Medicinal Chemistry, 1980, Vol.23, N o. 3a m i n e d , the R i s o m e r s u s u a l l y possess a h igher a f f in i tythan the S i somer ; however , f o r those a n a l o g u e s w h o s eracemates possess a low aff in i ty , th e eud ismic r a t io i s verysmall.Experimental Sect ionProton nuclear m agnetic resonance (N MR ) spectra were re-corded on a Perkin -Elmer R-24 high-resolution spectrom eter, an dchemical shiftsare reported relative to tetramethylsilane. Infraredspectra were obtained on a Perkin-Elmer 257 spectrophotometer,and mass spectra were de term ined using a Finnigan 4000-seriesGC /M S data system. Elem ental analyses were performed byAtlantic Microlab Inc., Atla nta, GA, and determ ined values arewithi n 0.4% of theor etica l values. All melt ing points were de-termined on a Thom as-Hoover melting point apparatus a nd areuncorrected. Unless otherwise sta ted all final prod ucts , listedin Tables I and 11, are HC1 salts.(*)-1-(2,4-Dimethoxypheny1)-2-aminopropane ydro-chloride (16). A solution of 43.HC1 (0.49 g, 2 mmol) in absoluteEtOH (50 mL) was shaken with P d/C ( lo % , 0 .1 g) under anatmosph ere of H 2 (45 psig) until 1equiv of H2was taken up. Thereaction mixture was filtered, and t he solvent was removed underreduced pressure to afford the crude product; recrystallizationfrom EtOH /EGO gave 0.37 g (76% ) of 43a as white crystals, mp235-236 "C (litenmp 219 "C). Anal. (CllHI7NO3~HC1), H, N.A mixture of 43a 0.31 g, 1.25 mmo l), Pd/B aSO , (5% , 0.03 g),HC104 (70% , 0.1 mL), and glacial HOAc (50 mL) was heated to85 "C and th en hydrogenated at 50 psig at room temperature for18.5 h. Th e solvent was removed under reduced pressure andthe residue was dissolved in 25 mL of H 20 . T he aqueo us solutionwas basified and extracted with E t 0 (2 X 10 mL) ; the E t2 0solution was dried (MgSO,) an d treated with HC1 gas to give crude16,m p 140-143 "C. Recrystalliza tion from EtO H afforded 0.05g (17% ) of 16,mp 150-152 "C. Anal. (CllH1,N02-HC1) C, H,N. Compound 16 was also prepared by reacting 2,4-dimethoxy-benzaldehyde with E tN 02 , ollowed by reduction of the resultingnitropropene 16b (m p 76-78 "C) ith LiA1H4. Though 16 hasbeen previously prepared in this manner,23no melting point ormicroanalytical data can be found in the literature.(f)-l-(2,3,5-Trimethoxyphenyl)-2-aminopropane28). Asolution of 2,3,5-trimethoxybenzaldehydeZ41.1g, 5.6 mmol),NH40Ac (0.5 g), and E t N0 2 (100mL ) was refluxed for 5 h. Thesolvent was removed under reduced pressure an d the product wasrecrystallized from M eO H/ Et OH to yield 0.9 g (64%) of 1-(2,3,5trimethoxyphenyl)-2-nitropropenes brigh t yellow crystals,m p 85-86 "C (lit.8m p 88"C). T he nitropropene (0.8g) was the nreduced w ith LiA1H4and converted to the HCl salt in a mannersimilar to that used by Shulgin.8N-[-(3,4,5-Trimethoxyphenyl)-2-nitropropyl]-3,4,5-tri-methoxybenzaldimine (33b). A solution of 3,4,5-trimethoxy-benza ldehy de (5.0 g, 25.5 mmo l), ammon ium aceta te (2.0 g, 25.9mmol), and nitroethane (17.2 g, 229 mmol) in benzene (125mL)was refluxed overnight. Th e yellow solution was washed with brine( 3 x 50 mL) and dried (Na 2S0 4), nd the solvent was removedin vacuo. Th e residue was crystallized by trituratio n with MeOH(15 mL ) and ligroin (30 mL ). Recrystallization from MeOHyielded 0.8g (15% based on starting aldehyde) of white crystals:mp 138-140 "C; NMR (CDC13)6 1.45 (d, 3 H , CH 3), 3.9 (s ,18 H,OCH 3), 4.5 (d, 1H, C H), 4.7 (m, 1H, CH), 6.75 (s, 2 H, Ar H),7.05 (s,2 H , Ar H ), 8.2 (s,1H, =CH); MS (70 eV) m/e (relativeinten sity) 448 (17), 374 (100). Anal. (CnHBN208) C,H, N. Therecrystallized mo ther liquor was removed in vacuo, yielding 4.1g of a yellow oil which solidified upon stan ding. Th is was iden-tified as 1-(3,4,5-trimethoxyphenyl)-2-nitropropene33a).1-(3,4,5-Trimethoxyphenyl)- -amino-2-nitropropane y -drochloride (33c).A solution of 33b 0.24 g, 0.53 mmol) in M eOH(10mL ) and aqueous HC 1(5% , 5 mL) was heated a t reflux for18 h. When th e solution cooled, MeOH was removed under(22) W. H. Hartung, J. C. Munch, E. Miller, and F. Crossley,J . A m .Chem. Soc., 53,4149 (1931).(23) K. Bailey, A. W. By, K. C. Graham, and D. Verner, Can. .Chem., 49, 3143 (1971).(24) J. R. Merchant, R. M. Naik, and A. J. Mountwalla, J . Chem.SOC., 14 2 (1957).

Glennon, Liebowitz, Andersonreduced pressure and the remaining aqueous mixture was ex-tracted with EBO (3 X 25 mL); the combined E h O solution wasdried (MgSOJ a nd evaporated to dryness to yield 100mg (96%)of 3,4,5-trimethoxybenzaldehydemp 71-73 "C). Th e aqueousportion was evaporated to dryness to yield crude 33c; ecrys-tallization from an MeOH-EBO mixture afforded 157 mg (96% )of 33c as a fine white powder, mp 194-196 "C dec. Anal. (Clz-(k)1 (2,5-Dimet oxy-3-met ylphenyl) 2-aminopropane(35). A solution of 35g (3 g, 12.6 mm ol) in an hydrou s EGO (100mL ) was added dropwise to a stirre d suspension of LiAlH, (1g,

25.3 mmol) in EGO (25 mL) a t 0 "C. After the solution was heatedat reflux for 6 h, NazSO4.10H20was added in small portions, at0 "C, until no further evolution of H2 occurred. Th e solvent wasevaporated under reduced pressure and the residual oil wasdistilled to give 1.1g (42 %) of 35asa colorless liquid, bp 115-118"C (0.3 mm). The oxalate salt was prepared by adding an an-hydrous EGO solution of the amine to a satur ated solution of oxalicacid in EGO: m p 231-233 "C afte r recrystallization from MeOH;NM R (free base, CDC13)6 1.1 (d, 3 H, CH3), 1.5 (d, 2 H, N H2) ,2.25 (s, 3 H , Ar CH 3), 2.7 (m , 3 H, CH, CHJ, 3.7 (s, 3 H, OCH3),3.75 (s,3 H , OCH3), 6.6 (8, 2 H, Ar H); M S (70 eV) m/e (relativeintens ity) 209 (5), 166 (100). Anal. [(C12H lgN0 2)2.(CO OH )2],H , N.2,5-Dimethoxy-3-methylbenzyl Alcohol (35d). 2-Hydroxy-3-methyl-5-methoxybenzyl lcohol (35b)was preparedby catalytic reduction of 15 g of 2,6-bis(hydroxymethyl)-4-methoxyphenol (35a) s previously reported.1 Wo rkup differedin that th e crude brown residue (13 g) was heated in a sublimationapp ara tus (0.1 mm, bath te mpe ratur e 80-100 "C) to yield ap-proximately 3.5 g of a sublimed produ ct as long white needles(mp 71 "C). This product was identified (NM R, mass spectrum)as being 2,6-dimethyl-l-hydroxy-4-methoxybenzene34c) lit.%m p 77 "C). Th e residual dark brown mass of crude 35bwas usedwithout fu rth er purification. An acetone solution of thi s residuewas methylated w ith Me1 as reported by Nichols e t al. 'O Inaddition to obtaining 5 g of the desired product 35b [b p 93-96"C (0.1mm), lit.lo 94-96 "C (0.1 mm )] in approximately 60% yield(based on 35a an d recovered byp roduc ts), 2 g of a lower boilingfractio n [b p 52-57 "C (0.09 mm )] was also isolated and charac-terized (NM R, mass spectrum) as 1,4-dimethoxy-2,6-dimethyl-benzene (35e), it.% bp 103 "C (10 mm).2,5-Dimethoxy-3-methylbenzaldehyde35f). A solution of35d (4 g, 22 mmol) in CH zClz 25 mL ) was adde d dropwise to astirred solution of freshly prepared pyridinium chlorochromate(7 g, 33 mmol) in CH2C12 250 mL) a t room tem pera ture . Afteranhydrous EGO (100mL) was added, stirring was continued foran additional 15 min. Th e solvent was decanted an d filteredthrou gh a thick pad of Florisil (100-200 mesh) to yield a pale-yellow solution. (In a separate experim ent, the use of 30-6O-meshFlorisil resulted in a brown solution from which no crystallineprod uct was isolated.) Solvent was removed under reducedpressure t o yield 3.8 g (9 6% ) of 35f as white crystals after re-crystallization from hexane, m p 42-44 "C, lit.1om p 42.5-43 "C.l-(2,5-Dimethoxy-3-methylphenyl)-2-nitropropene35g).A solution of 35f 5 g, 27.7 mmol), N H4 0A c (2.1 g, 27.7 mm ol),and EtNO, (100mL ) was refluxed for 5 h. Solvent was removedunder redu ced pressure; t he crud e product was dissolved in E g O(75 mL ), washed with sat urate d NaCl solution (3 X 50 mL) an ddried (MgSO,), an d the solvent was evaporated in vacuo. Re-crystallization of th e pro duct from MeO H gave 5.5 g (84 %) of35g as bright-yellow needles, mp 92-93 "C. Anal. (C12H16N0d)C, H, N.(f)-1-(2,5-Dimethoxy-3-bromophenyl)-~-aminopropane(36). A solution of AlH3 in T H F was prepared by t he dropwiseaddition of a solution of 0.1 mL (0.188 g, 1.92 mmol) of 100%H2 S04 n 10 mL of TH F to a stirred suspension of LiAlH, (0.15g, 3.84 mmol) in TH F (75 mL) at 0 "C under an atm osphere ofN2. Without removing the precipitated Li2S04,a solution of 36c(400 mg, 1.32 mmol) in T H F (50 mL ) was added over a 30-minperiod. After the solution was stirred a t room tem perature for

H18N205.HCl) C, H , N .

(25) W. Reeve and A. Sadle, J . A m . Chem.Soc., 72,3252 (1950).(26) A. A. R. Sayigh,H. Ulrich, and M. Green, J . Chem.Soc., 3482(1964).


6/6

Receptor Affini t ies of Phenalkylamine Analoguesan additional hour, the excess hydride was decomposed by theaddition of small chips of ice, followed by 10 % NaOH solutionuntil a white precipitate resulted. T he m ixture was filtered undersuction, and the filter cake was washed several times with TH F.The solvent was evaporated under reduced pressure and theresidual oil was distilled [Kugelrohr,80-90 "C (0.14 mm)] to give36 as a colorless liquid. Th e oxalate salt was prepared by addingan anhydrous EhO olution of the amine to a saturated solutionof oxalic acid in Eb O: mp 232-234 OC after recrystallization fromMeOH; NMR (DzO)6 1.3 (d , 3 H, C H d , 2.95 (m , 3 H, CH2,C H) ,3.85 ( s , 6 H,-OCH3),6.95 (s, 1 H , Ar H ), 7.30 (s, 1 H, Ar H) ;M S(70 eV) m / e (relative intensity) 276 (46), 274 (4 8), 77 (100 ). Anal.[ ( C l l H , ~ N O ~ Br ) ~ . ( CO O H ) ~ l, H, N.2,5-Dimethoxy-3-bromobenzaldehyde36b). Methylationof 2-hydroxy-3-bromo-5-methoxybenzaldehyde 36a)27 wasachieved only with great difficulty according to the followingprocedure: A solution of 4 g of NaO H in 70 mL of MeOH wasadde d dropwise to a stirr ed refluxing soluti on of 36a (7 g, 30 mmol)and Me1 (50mL) in 150 mL of a 5050 mixture of MeO H/EtO Hwith th e formation of an insoluble precipita te of the phenoxidesalt. Refluxing was continued for 2 days, after which time 50 mLof Me1 was added dropwise. Following 2 more days of additi onalheating, a solution of 8 g of NaO H in MeO H (150 mL) was addeddropwise to the reaction mixture. After 2 more day s of heatinga t reflux, the addit ion of M eI, followed by Na OH described above,was repeated. Subsequently, he reaction was terminated, solventwas removed under vacuum, HzO (200 mL) was added, and thepH was adjusted to 12 by the addit ion of 4 N NaOH. The aqueousreaction mixture was then e xtracted twice with CHzClz 10 0 mL).Th e com bined organic extracts were then extracted with 100 mLof 2 N N aOH. The solvent was evaporated, resulting in an oilymaterial towhich 100 mL of MeOH was added . Again he solventwas removed by slow evaporat ion under vacuum , yielding a crudecrystalline product (5.6 9). Recrystallization from MeOH gave5.2 g ( 6 7 % ) of 36 b as white needles, mp 64-65 "C, lit.27m p 63"C .1 (2 ,5-Dimethoxy-3-bromophenyl)-2-nitropropene36c) .Compound 36c was prepared in 87% yield in a manner similarto th at used for 35g. Recrystallization of the prod uct from ab-solu te EtO H gave 36 c as yellow needle s, mp 79-80 OC. Anal.(C1J-k"Br) C, H, N.A f f i n i t y A s s a y S t u d i e s . Sprague-Dawley ra ts (Flow Labs;Dublin , VA) of eithe r sex, weighing 2OC-250 g, were used. Th erat stomach fundus preparation employed was essentially tha tof VaneB w ith t he previously described modifications! Two strips(27) L. Rubenstein, J . Chem. Soc., 127, 1998 (1925).

Journal of Medicinal Ch emistry , 1980, Vol. 23 , No. 3 29 9were cut from the same tissue an d used in parallel 8-mL musclebaths. The relative sensitivity of the two strips was determined,after a 1-h equilibration period, by the use of 5-H T doses givingsubmaxim al contractions. Only one compound was tested perpreparation, the second strip serving as control.The ability or potency of each agent to inhibit the contractileresponse of 5-HT was determined by obtaining cumulativedose-response curves to 5-H T (a t 7-9 concentrations of 5-HTranging from approxim ately 1 nm to 10 pm), first in th e absenceof th e agent in question and th en in th e presence of increasingconcentrations thereof. Compoun ds 1-45 were examined aminim um of twice at each of usually four different conc entrati ons.Th e ED, of 5-H T was determined for each of the curves and th eappare nt affinities were calculated as pAz values by the methodof Arunlakshana and Schild.29 In addition, Schild plots weresubjected to linear-regression analysis in order to determine slopes(which usually ranged from -0.8 to -1.2, with the exception ofcompound 44). At high enough concentrations, certain compoundsproduced an agonistic response; all attempts were made to avoidsuch high concentrations.

Acknowledgment. This work was supporte d, in part,by U S . Public Health Service Grant DA-01642. We alsoexpress our appreciation to NIDA, the United NationsNarcotics Laboratory, and Dr. E. May for the gift of com-pounds 41 and 44 , to Dr. J. D. Smith for compounds 40,42, and 43, toE. C. Mack for her able technical assis tanc e,and to Dr. Larry Jaques of A. H. Robins for the 13C NM Rspectra on compound 33b.(28) J. R. Vane, Br . J.Pharmacol., 14, 87 (1959).(29) 0. Arunlakshana and H. 0. Schild,Br. J. Pharmacol., 14 ,48(30) T. B. Johnson and H. H. Guest, Am. Chem. J.,42,34 6 (1909).(31) J. B. Shoesmith and R. J. Conner,J. Chem. Soc., 2232 (1927).(32) K. H. Slotta and H. Heller, Chem. Ber., 63B, 3029 (1930).(33) K. Ciesielski, Chem. Zentralbl., 1793 (1907).(34) J. S. Buck, J . A m . Chem. Soc., 54, 3661 (1932).(35) D. E. Nichols, C. F. Barfnecht, D. B. Rusterholz, F. Benington,and R. D. Morin, J. Med. Chem., 16, 480 (1973).(36) B. T. Ho, W. M. McIsaac , R. An, W. Tansey, K. E. Walker, L.F. Englert, and M. B. Noel, J. Med. Chem. , 13, 26 (1970).(37) F. Benington, R. D. Morin, L. C. Clark, Jr., and R. P. Fox, J.Org. Chem., 23, 1979 (1958).(38) A. T. Shulgin, Experientia, 20, 336 (19 64).(39) J. S. Buck, J . Am. Chem. SOC., 5, 3388 (1933).(40) J. Tafel, Chem. Ber., 22, 1854 (1889).

(1959).

serotonin receptor affinities of psychoactive phenalkylamine analogues

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