TN- March 1992 Wol. 131 85

A proposal for the classification of sigma binding sites

Until relatively recently, it was difficult to distinguish pharma- cologically the binding site for phencyclidine from the ‘d site. While it is now clear that the former is part of the NMDA re- ceptor complexl, the status of the o site remains unclear’. Although few data are available to indicate a functional role for this site (but see belowj, the high levels of ‘o’ bind- ing in various limbic structures~5, and the high affinity of some neuroleptics (e.g. haloperidol and remoxipride) for these sites”‘, have excited interest in the possi- bility of creating a new class of antipsychotic drug, devoid of do- paminergic activity, that binds selectively to o site@-lo. This po- tential therapeutic endpoint has fuelled extensive research into these sites (see, for example, Refs 2, 8-16) and much of this work has indicated that more than one sub- type of o site may exist13,“,‘G23. This possible heterogeneity has generated confusion in the litera- ture as putative subtypes were classified according to unspecified criteria. It was partly to remedy this situation that a committee was created at a recent international meeting on sigma drugs* to pro- pose guidelines towards the classi- fication of o sites. The consensus proposal is outlined below.

Sigma subtypes Much of the evidence for the

existence of subtypes of o sites is based on data obtained from bio- chemical and ligand-binding ex- periments rather than experiments where a functional endpoint was measured. Thus the sites that have been distinguished should not yet be referred to as receptors.

Taking into account most of the current literature in the field, the committee proposed that subtypes

*The Third United States-French-sponsored International Seminar on Phencyclidine and Sigtna Drugs, La Crunde Motte, Montpellier, France, 16-20 September 1991 b

of o binding sites be classified as shown in Table I (e.g. see Refs 11-13 16-23). The most commonly used o iigands, including halo- peridol and DTG, are not able to discriminate between o1 and 9 subtypes. By contrast, the pure stereoselective isomers of pentaz- ocine and SK&F10047 are much more selective in that regard17*18,21. While (+)-pentazocine and (+)- SK&F10047 demonstrate high (nanomolar) affinity for o1 sites, they possess only low (micromolar) affinity for 9 sites. (-) Isomers of these two compounds demonstrate only low to moderate affinities for these sites, without distinguishing between them. Thus, a reverse stereoselectivity profile is observed for these two pairs, the (+) isomers being much more potent on the oi site [( +) >> (-)] while the opposite situation is observed on 9 sites

[(-) >> (+)I. A recent study has shown that a series of more than 15 enantiomeric pairs of novel beruo- morphans tested in different tissues behave similarlyr4.

Other important tools allowing a clear dissociation between o1 and 9 sites include carbetapentan$l, dextromethorphan”~~~7 and phenytoirW=‘*~. Both carbeta- pentane and dextromethorphan behave as rather selective ol ligands while phenytoin can allo- sterically modulate the o1 subtype without affecting 9 sites. More- over, binding to al sites, under certain assay conditions”*14’PB, is sensitive to the modulatory effects of GTP and its metabolically stable analogues, while binding to 9 sites is usually resistant*6.23. Additionally, or, but not 02 bind- ing is usually decreased following a subchronic three-week treatment with haloperidol”.

Limited functional data on the respective role of ul and u2 sites are available. While various biological effects have been attributed to actions at (7 sites, it is unclear if those are genuine sigma effects or related to the poor selectivity and specificity of the tested compounds [e.g. haloperidol, (+)3-PPP] for u

TABLE I. Proposed classification scheme for sigma binding sites

Ligand or assay 03 9

Discriminani ligands (+)-Pentazocine (+)-SK&F10047 Carbetapentane Dextmmethorphan

Nondiacrlminant llgandr Haloperidol DTG (+)-3-PPP (-)-Pentazocine (-)-SK&F10047 Naloxone

Other characteriatlcs Phenytoin sensitivity GTP sensitivity Decrease in binding followino subchronic

high affinity moderate to high affinity high affinity moderate to high affinity

high affinity high affinity high affinity tow to moderate affinity low affinity inactive

Yes yes’ yest

low affinity very low afftntty very low affinity very low affinity

high afflnlty high aftinky moderate to high affimty low to moderate afffntty low affinity inactfve

no no no

halope&fol Functional assays

Radlollgands

various gastrointestinal dystonia upon injection affects; inhibition of into the rat red nucleus: contraction of guinea- modulation of K+ channelss pig ileum; inhibition of acetylcholine-induced phosphoinosfkde response*

[3H](+)_pentazocine PHIDTG (in presence of blockers)n

‘Exceptions cannot be excluded at present: dependent on pH and incubation buffer con- ditions’s*ti*p. t Also reported to occur acutely, after a single injection of reduced haloperfdol, a potent metabollte of haloperidol on u sites 38-m. *A direct action of sigma drugs on muscarinic acetylchollne receptors cannot be fully excluded; however, sigma ligands have reduced efficacy in cells lacking a, sites3 5, sStereospeclflcity of putative functional 0s effects remains to be fully established. %[3H]DTG in presence of a saturating concentration (at least 500-1000 nM) of either (+)-pentazocine, (+)-SK&F10047 or dextrallorphans’r.

& 1992, Elsevier Science Publishers Ltd (UK)

TiPS - March 1992 [Vol. 131

sites. However, preliminary data suggest that more selective sigma drugs such as JO17843’, which has low affinity for dopamine re- ceptors, induce various in vitro and in z~ieo gastrointestinal effects by activating ol sites=-. In the guinea-pig ileum, sigma drugs in- hibit both electr; =‘ly and 5-HT- induced contractions, most likely by acting on ul sites14%. Moreover, al sites appear to mediate the inhibition by sigma ligands of the muscarinic acetylcholine receptor phosphoinositide responseX. However, the possibility that a direct action on muscarinic re- ceptors may contribute to the in- hibition cannot be fully excluded. On the other hand, sigma ligands, most likely by acting on oz sites, produced a dystonic posture upon microinjection into the red nucleus of the rat*4.36. 9 sites may also mediate the effects of certain sigma drugs on K+ channels13J9. Studies are currently in progress in order to provide additional evidence on the functional role mediated by q and 9 sites.

Finally, much confusion on the characterization of subtypes of o sites arises from the use of non- selective radioligands. Fortunately, the recent development of a sel- ective (~1 ligand, [3H](+)-pen- tazocine3’, should be helpful although the complete character- istics of the o1 site should also be demonstrated in other types of studies. Selective o2 ligands are still not available. [3H]DTG38, in the presence of a q site blocker41 (Table I), may prove useful as a tentative approach to investigate 9 sites.

The 01 and 9 subtypes of o binding site demonstrate unique ligand selectivity profiles and are differentially modulated following various treatments. We now hope that the classification proposed here will be generally accepted. This would facilitate discussion and help to clarify their putative functional roles.

B&l QUIBION*, WAYNE D. BOWEN,

YOSSEF ITZHAK, JEAN LOUIS JUNIEN,

JOSk M. MUSACCHIO,

RICHARD B. ROTHMAN,

TSUNG-PING SU, S. WILLIAM TAM

AND DUNCAN P. TAYLOR

*Douglas Hospital Research Centre, and Department of Psychiatry, McGill University, 6875 Blvd LnSalle, Verdun, Qu&ec, Canada H4H ZR3.

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Erratum Multiple benzodiazepine re- ceptors: no reason for anxiety, by Adam Doble and lan L. $4a& (February 2992, pp.

The compound Ro154513 was incorrectly referred to as sarmazenil throughout this article. Ro154513 does not yet have a generic name. This error originated in the TiPS office and we apologise for any confusion which may have been caused.

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DTG: ditolylguanidine JO17&I: (+) N-cyclopropylmethyl-N- methyl-1,4-diphenyl-I-ethyl-but-3-en-l- ylamine hydrochloride (+)-3-PPP: (+)-3-(3-hydroxyphenyl)-N-(l- propyl)piperidine SK&FlOO47: (f)-N-allylnormetazocine

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