Chemical synthesis and molecular pharmacology of hydroxylated 1-(1-phenylcyclohexyl-piperidine derivatives

Abstract

The following monohydroxy derivatives of 1-(1-phenylcyclohexyl)piperidine (phencyclidine, PCP) were synthesized: o-, m-, and p-phenols of PCP, 1-(1-phenylcyclohexyl)-4-piperidinol, and two stereoisomeric pairs of 3-phenyl-3-(1-piperidinyl)cyclohexanol and 4-phenyl-4-(1-piperidinyl)cyclohexanol. Inhibition of specific binding of tritiated PCP, morphine, or quinuclidinyl benzylate (QNB) in rat brain homogenates was measured for these compounds. Inhibition of PCP binding for selected compounds correlated with mouse rotarod assay activity. The most characteristic effects of hydroxylation of PCP on the cyclohexyl, piperidine, or phenyl moieties are the following: (i) it generally decreases its activity in inhibiting [3H]PCP binding by a factor of 10 to 80; (ii) it does not produce a large variation in the affinity for the morphine receptor; (iii) it produces a considerable decrease of the affinity for the muscarinic receptor. An important exception to these general observations was the metaphenolic derivative of PCP. This PCP derivative has an affinity for the [3H]PCP binding sites that is 8 times higher than that of PCP itself; its affinity for the muscarinic receptor is only twice lower than that of PCP, but its affinity for the morphine receptor is 430 times higher than that of PCP and only one order of magnitude lower than that of morphine itself.