Alterations in the stereochemistry of the kappa-selective opioid agonist U50,488 result in high-affinity sigma ligands

The synthesis and in vitro sigma receptor activity of the two diastereomers of U50,488 (+/-)-2], namely, (1R,2S)-(+)- cis-3,4-dichloro-N-methyl-N-2-(1-pyrrolidinyl)cyclohexyl]benzeneacet ami de (+)-1] and (1S,2R)-(-)-cis-3,4-dichloro- N-methyl-N-2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (-)-1], are described. (+)-1 and (-)-1 were synthesized from (+/-)-trans-N-methyl-2-aminocyclohexanol (+/-)-3]. Pyridinium chlorochromate (PCC) oxidation of the N-t-Boc-protected derivative of (+/-)-3 afforded (+/-)-2-N- (tert-butyloxy)carbonyl]-N-methylamino]cyclohexanone (+/-)-5]. The sequence of enamine formation with pyrrolidine, catalytic reduction, N-deprotection, and optical resolution afforded (1R,2S)-(-)-cis-2-pyrrolidinyl-N-methylcyclohexylamine (-)-10] and (1S,2R)-(+)-cis-2-pyrrolidinyl-N-methylcyclohexylamine (+)-10]. The optical purity (greater than 99.5%) of (-)-10 and (+)-10 was determined by HPLC analysis of the diastereomeric ureas formed by reaction with optically pure (R)-alpha-methylbenzyl isocyanate. The absolute configuration of (-)-10 and (+)-10 was determined by single-crystal X-ray diffractometry of the bis-(R)-mandelate salt. Condensation of optically pure (-)-10 and (+)-10 with 3,4-dichlorophenylacetic acid furnished (+)-1 and (-)-1, respectively. Compounds (+)-1, (-)-1, (-)-2, and (+)-2 were compared for their binding affinities at kappa opioid, sigma, D2-dopamine, and phencyclidine (PCP) receptors in competitive binding assays using 3H]bremazocine (3H]BREM) or 3H]U69,593, 3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine 3H]-(+)-3-PPP], or 3H]-1,3-di(o-tolyl)guanidine (3H]DTG), 3H]-(-)-sulpiride 3H]-(-)SULP], and 3H]-1- 1-(2-thienyl)cyclohexyl]piperidine (3H]TCP), respectively. In the systems examined, (-)-2 exhibited the highest affinity for kappa receptors, with a Ki of 44 +/- 8 nM. However, (-)-2 also showed moderate affinity for sigma receptors, with a Ki of 594 +/- 3 nM 3H]-(+)-3-PPP]. The (1R,2R)-(+)-enantiomer, (+)-2, had low affinity for both kappa and sigma receptors, exhibiting Ki values of 1298 +/- 49 nM at kappa (3H]BREM) and 1270 +/- 168 nM at sigma 3H]-(+)-3-PPP]. In contrast, the chiral cis compounds (+)-1 and (-)-1 showed high affinity for sigma receptors and negligible affinity for kappa opioid receptors in the 3H]BREM assay. Compound (-)-1 exhibited a Ki of 81 +/- 13 nM at sigma receptors 3H]-(+)-3-PPP] and 250 +/- 8 nM (3H]DTG).(ABSTRACT TRUNCATED AT 400 WORDS)