DPP IV inhibitor blocks mescaline-induced scratching and amphetamine-induced hyperactivity in mice

A potent inhibitor of the enzyme dipeptidyl peptidase IV (DPP IV), called AMAC, reduced psychosis-like behaviors in two animal models. In mice given mescaline, AMAC decreased scratching paroxysms by up to 68% depending on dose. In mice given amphetamine, AMAC reduced hyper-locomotion by up to 76%. A similar compound that does not inhibit DPP IV had no effect. AMAC also did not bind to 20 receptors linked to schizophrenia, including dopamine, serotonin, and glutamate receptors. These results suggest that blocking DPP IV may produce antipsychotic effects through a novel mechanism.

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Abstract

Dipeptidyl peptidase IV (DPP IV) is a ubiquitous membrane-bound enzyme that cleaves the two N-terminal amino acids from peptides with a proline or alanine residue in the second position from the amino end. Potential substrates for DPP IV include several neuropeptides, suggesting a role for DPP IV in neurological processes. We have developed a potent DPP IV inhibitor (IC50 = 30 nM), 1-(2-amino-3-methyl-butyryl)-azetidine-2-carbonitrile (AMAC), which has shown efficacy in two established models of psychosis: mescaline-induced scratching and amphetamine-induced hyperactivity. In the mescaline-induced scratching model, AMAC treatment before mescaline administration reduced the number of scratching paroxysms by 68% (P < 0.01). The compound showed a dose-dependent effect, inhibiting significantly at 6, 20 and 60 mg/kg (37%, 39% and 68%, respectively). In the amphetamine-induced hyperactivity model, 50 and 60 mg/kg AMAC, given before injection of amphetamine, significantly reduced hyper-locomotion by 65% and 76%, respectively. Additionally, AMAC showed no significant activity in binding assays for 20 receptors thought to be involved in the pathology of schizophrenia, including dopamine, serotonin and glutamate. A structurally similar analog, 1-(2-dimethylamino-3-methyl-butyryl)-azetidine-2-carbonitrile (DAMAC), that does not inhibit DPP IV, was inactive in both models. Taken together, these data suggest that the antipsychotic effects of AMAC are the result of DPP IV inhibition.