Synthesis and evaluation of N-substituted cis-N-methyl-2-(1-pyrrolidinyl)cyclohexylamines as high affinity σ receptor ligands. Identification of a new class of highly potent and selective σ receptor probes

Article abstract of DOI:10.1021/jm00173a030

Certain benzeneacetamides [(-)- and (+)-cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzenea cetamide] 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-methylcyclohexylamines, were synthesized and their structure-activity requirements were determined. The compounds were synthesized by starting with the previously reported (±)-, 1S,2R-(+)-, and 1R,2S-(-)-cis-2-(1-pyrrolidinyl)-N-methylcyclohexylamines. Analysis of σ ([³H](+)-3-PPP), κ ([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, 1S,2R-cis-(-)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-(2-naphthyl)ac etamide [(-)-29] (K(i) = 8.66 ± 0.35 nM), (±)-cis-2-amino-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl ]benzeneacetamide [(±)-17] (K(i) = 11 ± 3 nM), 1S,2R-(-)-cis-N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidin yl)cyclohexylamine [(-)-44] (K(i) = 1.3 ± 0.3 nM), and 1R,2S-(+)-cis-N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidin yl)cyclohexylamine. [(+)-44] (K(i) = 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 significant affinity for κ, 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.