Metaphit, a derivative of
phencyclidine (PCP), irreversibly binds to PCP sites in rat brain homogenates. PCP-induced
catalepsy in pigeons, which is a pharmacologically specific and stereoselective phenomenon, was used to study pharmacological consequences of the proposed covalent bonding of
metaphit to PCP sites.
Metaphit pretreatment increased the cataleptic effects induced by cumulative doses of PCP-type drugs (i.e., PCP,
ketamine and
m-amino PCP) and of drugs that have PCP-like actions (i.e.,
dexoxadrol, LY 154716 and
cyclazocine).
Metaphit did not affect
pentobarbital-induced loss of righting, head-drop and eye closure.
Metaphit itself induced a PCP-like
catalepsy. Isobolographic analysis of the interactions between
metaphit and PCP-like drugs suggested that
metaphit potentiated the
catalepsy-inducing effects of these drugs. The possibility that
metaphit exerts its potentiating effects by inhibition of PCP biotransformation was evaluated by measuring plasma and brain concentrations of PCP after pretreatment with either
metaphit or
SKF-525A, an inhibitor of the
enzyme systems involved in PCP biotransformation.
SKF-525A, but not
metaphit, increased brain levels of PCP. The results suggest that
metaphit acts not as an antagonist of PCP but as a less-potent, long-acting, specific PCP-like agonist. Potentiation by
metaphit of the cataleptic effects of chemically diverse drugs with PCP-like actions does not appear to be based on inhibition of the
enzyme systems involved in metabolism of those drugs.