DPP IV inhibitor blocks mescaline-induced scratching and amphetamine-induced hyperactivity in mice.
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.
Lautar
Susan L
SL
Guilford Pharmaceuticals, Inc., 6611 Tributary Street, Baltimore, MD 21224, USA. lautars@guilfordpharm.com
Rojas
Camilo
C
Slusher
Barbara S
BS
Wozniak
Krystyna M
KM
Wu
Ying
Y
Thomas
Ajit G
AG
Waldon
Daniel
D
Li
William
W
Ferraris
Dana
D
Belyakov
Sergei
S
D000661:Amphetamine; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001384:Azetidines / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006220:Haloperidol / Q000494:pharmacology; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy*; D006967:Hypersensitivity / Q000188:drug therapy* / Q000209:etiology; D020128:Inhibitory Concentration 50; D008297:Male; D008635:Mescaline / Q000633:toxicity; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017366:Serotonin Receptor Agonists / Q000633:toxicity; D013997:Time Factors
C503634:1-(2-amino-3-methyl-butyryl)-azetidine-2-carbonitrile; D001372:Aza Compounds; D001384:Azetidines; D018492:Dopamine Antagonists; D009570:Nitriles; D017366:Serotonin Receptor Agonists; D000661:Amphetamine; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D006220:Haloperidol; D008635:Mescaline