SYNTHESIS AND EVALUATION OF N-SUBSTITUTED CIS-N-METHYL-2-(1-PYRROLIDINYL)CYCLOHEXYLAMINES AS HIGH-AFFINITY SIGMA-RECEPTOR LIGANDS - IDENTIFICATION OF A NEW CLASS OF HIGHLY POTENT AND SELECTIVE SIGMA-RECEPTOR PROBES

Certain benzeneacetamides [(-)- and (+)-cis-3,4-dichloro-N-methyl-N-[2-(l-pyrrolidinyl)cyclohexyl]benzeneacetamide] were recently reported to be potent σ receptor ligands. In order to determine whether efficacy for the σ receptor could be improved, a series of compounds related to the benzeneacetamides, N-substituted cis-2-(1-pyrrolidinyl)-N-methylcyclohexylainines, were synthesized and their structure-activity requirements were determined. The compounds were synthesized by starting with the previously reported (±)-, 1S,2R-(+)-, and lR,2S-(-)-cis-2-(l-pyrrolidinyl)-N-methylcyclohexylamines. Analysis of σ ([3H](+)-3-PPP), K ([3H]bremazocine and [3H]U69,593), dopamine-d2([3H](—)-sulpiride), and phencyclidine (PCP) ([3H]TCP) receptor binding in guinea pig brain revealed a number of highly potent and selective σ receptor ligands. Notably, lS,2R?-cis-(-)-N-methyl-N-[2-(l-pyrrolidinyl)cyclohexyl]-(2-naphthyl)acetamide [(—)-29] (Ki= 8.66 ± 0.35 nM), (±)-as-2-amino-4,5-dichloro-N-methyl-N-[2-(l-pyrrolidinyl)cyclohexyl]benzeneacetamide [(±)-17] (Ki= 11 ± 3 nM), 1S,2R?-(-)-cis-N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(l-pyrrolidinyl)cyclohexylamine [(—)-44] (Ki= 1.3 ± 0.3 nM), and 1R,2S-(+)-cis N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(l-pyrrolidinyl)cyclohexylamine. [(+)-44] (Ki= 6 ± 3 nM) exhibited very high affinity at σ receptors, by displacement of [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H]-(+)-3-PPP). These compounds showed insignificant affinity for k, dopamine, or PCP receptors, making them valuable tools for the study of σ receptors. Furthermore, these compounds also exhibited enantioselectivity ranging from 5-fold for (+)- and (-)-44 to 160-fold for (+)- and (~)-29. Several other compounds showed equivalent selectivity but displayed lower σ receptor affinity. © 1990, American Chemical Society. All rights reserved.