Sensitivity of the PCP receptor and the dopamine transporter to ligands bearing multiple asymmetric centres

Abstract

Summary Generation of one or two asymmetric carbons by means of a methyl substitution into cyclohexyl or piperidine moieties of 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) and 1-[1-(2-benzo[ b ]thiophenyl)cyclohexyl]piperidine (BTCP) structures has revealed improved affinity and/or selectivity for the PCP receptor and the dopamine (DA) transporter, respectively. Therefore, to get more information about the influence of chiral centres on affinity and selectivity, simultaneous methyl substitutions of cyclohexyl and piperidine moieties have been performed to generate three asymmetric carbons into the parent structures. Thus, cis -(Pip/Me)-1-[1-(2-thienyl)-2-methylcyclohexyl]-3-methylpiperidines and cis -(Pip/Me)-1-[1-(2-benzo[ b ]thiophenyl)-2-methylcyclohexyl]-3-methylpiperidines in homochiral forms have been prepared and their affinities for the PCP receptor ([ 3 H]TCP binding) and for the DA transporter ([ 3 H]BTCP binding) have been measured on rat brain and striatal membranes, respectively. None of the enantiomeric structures revealed affinities and/or selectivities in the same range as molecules bearing one or two asymmetric centres. In the TCP series the best compounds were in the same range as the parent compound. In the BTCP series, pure stereomers displayed lowered affinities and considerably reduced selectivities than the parent compound.