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

Article abstract of DOI:10.1021/jm00128a050

The synthesis and in vitro σ receptor activity of the two diastereomers of U50,488 [(±)-2], namely (1R,2S)-(+)-cis-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide [(+)-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,2R)-(-)-cis-2-pyrrolidinyl-N-methylcyclohexylamine [(-)-10] and (1S,2R)-(+)-cis-2-pyrrolidinyl-N-methylcyclohexylamine [(+)-10]. The optical purity (>99.5%) of (-)-10 and (+)-10 was determined by HPLC analysis of the diastereomeric ureas formed by reaction with optically pure (R)-α-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 κ opioid, σ, 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 κ receptors, with a K(i) of 44 ± 8 nM. However, (-)-2 also showed moderate affinity for σ receptors, with a K(i) of 594 ± 3 nM [[³H]-(+)-3-PPP]. The (1R,2S)-(+)-enantiomer, (+)-2, had low affinity for both κ and σ receptors, exhibiting K(i) values of 1298 ± 49 nM at κ ([³H]BREM) and 1270 ± 168 nM at σ [[³H]-(+)-3-PPP]. In contrast, the chiral cis compounds (+)-1 and (-)-1 showed high affinity for σ receptors and negligible affinity for κ opioid receptors in the [³H]BREM assay. Compound (-)-1 exhibited a K(i) of 81 ± 13 nM at σ receptors [[³H]-(+)-3-PPP] and 250 ± 8 nM ([³H]DTG). The corresponding values for (+)-1 were 221 ± 36 nM [[³H]-(+)-3-PPP] and 118 ± 7 nM ([³H]DTG). Compounds (-)-2 and (+)-2 lacked affinity for D₂-dopamine receptors. Compounds (+)-1 and (-)-1 bound only weakly to D₂-dopamine receptors, displaying K(i) values of 14039 ± 1429 nM and 3762 ± 829 nM, respectively. All of the compounds lacked affinity for PCP receptors.