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
| Autor: | B R, de Costa, K C, Rice, W D, Bowen, A, Thurkauf, R B, Rothman, L, Band, A E, Jacobson, L, Radesca, P C, Contreras, N M, Gray |
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| Rok vydání: | 1990 |
| Předmět: |
Pyrrolidines
Chemical Phenomena medicine.drug_class Stereochemistry Guinea Pigs Sigma receptor Benzeneacetamides Carboxamide Cyclohexylamine Binding Competitive Receptors Dopamine Structure-Activity Relationship chemistry.chemical_compound Cyclohexanes Drug Discovery medicine Animals Receptors sigma Pyrroles Receptor Molecular Structure Receptors Dopamine D2 Receptors Opioid kappa Brain Stereoisomerism Rats Receptors Neurotransmitter Benzomorphans Chemistry chemistry Receptors Opioid Bremazocine Molecular Medicine Receptors Phencyclidine Piperidine Acetamide |
| Zdroj: | Journal of Medicinal Chemistry. 33:3100-3110 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00173a030 |
| Popis: | Certain benzeneacetamides [(-)- and (+)-cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide] were recently reported to be potent sigma receptor ligands. In order to determine whether efficacy for the sigma 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 sigma ([3H](+)-3-PPP), kappa ([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 sigma receptor ligands. Notably, 1S,2R-cis-(-)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-(2-naphthyl) acetamide [(-)-29] (Ki = 8.66 +/- 0.35 nM), (+/-)-cis-2-amino-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide [(+/-)-17] (Ki = 11 +/- 3 nM), 1S,2R-(-)-cis-N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl ) cyclohexylamine [(-)-44] (Ki = 1.3 +/- 0.3 nM), and 1R,2S-(+)-cis-N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl ) cyclohexylamine. [(+)-44] (Ki = 6 +/- 3 nM) exhibited very high affinity at sigma receptors, by displacement of [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [( 3H]-(+)-3-PPP). These compounds showed insignificant affinity for kappa, dopamine, or PCP receptors, making them valuable tools for the study of sigma 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 sigma receptor affinity. |
| Databáze: | OpenAIRE |
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