TY - JOUR
T1 - DPP IV inhibitor blocks mescaline-induced scratching and amphetamine-induced hyperactivity in mice
AU - Lautar, Susan L.
AU - Rojas, Camilo
AU - Slusher, Barbara S.
AU - Wozniak, Krystyna M.
AU - Wu, Ying
AU - Thomas, Ajit G.
AU - Waldon, Daniel
AU - Li, William
AU - Ferraris, Dana
AU - Belyakov, Sergei
PY - 2005/6/28
Y1 - 2005/6/28
N2 - 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.
AB - 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.
KW - Amphetamine-induced hyperactivity
KW - CD26
KW - DPP IV
KW - Enzyme inhibition
KW - Mescaline-induced scratching
KW - NPY
KW - Peptide
KW - Psychosis
KW - Schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=20444395442&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20444395442&partnerID=8YFLogxK
U2 - 10.1016/j.brainres.2005.04.069
DO - 10.1016/j.brainres.2005.04.069
M3 - Article
C2 - 15925329
AN - SCOPUS:20444395442
VL - 1048
SP - 177
EP - 184
JO - Brain Research
JF - Brain Research
SN - 0006-8993
IS - 1-2
ER -