SENSITIVITY OF THE PCP RECEPTOR AND THE DOPAMINE TRANSPORTER TO LIGANDS BEARING MULTIPLE ASYMMETRIC CENTERS

Generation of one or two asymmetric carbons by means of a methyl subst itution into cyclohexyl or piperidine moieties of 1-[1-(2-thienyl)cycl ohexyl]piperidine (TCP) and 1-[1-(2-benzo[b]thiophenyl)cyclohexyl]pi ( BTCP) structures has revealed improved affinity and/or selectivity for the PCP receptor and the dopamine (DA) transporter, respectively. The refore, to get more information about the influence of chiral centres on affinity and selectivity, simultaneous methyl substitutions of cycl ohexyl and piperidine moieties have been performed to generate three a symmetric carbons into the parent structures. Thus, 2-thienyl)-2-methy lcyclohexyl]-3-methylpiperidines and cis-(Pip/Me)-1-[1-(2-benzo [b]thi ophenyl) -2-methylcyclohexyl]-3-methylpiperidines in homochiral forms have been prepared and their affinities for the PCP receptor ([H-3]TCP binding) and for the DA transporter ([3H]BTCP binding) have been meas ured on rat brain and striatal membranes, respectively. None of the en antiomeric 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 com pound. In the BTCP series, pure stereomers displayed lowered affinitie s and considerably reduced selectivities than the parent compound.