B. J. CALDARONE, C. MACK, T. HANANIA, D. BRUNNER, M. SAMANT, D. PARKES, V. SRIVASTAVA, M. HANLEY, P. MCGONIGLE, W. ROTE, B. OLIVIER, A. GHAVAMI
Peptide hormones possess appealing drug profiles based on their role as natural integrators of physiological systems. We have recently discovered antidepressant-like effects of the peptide hormone amylin in both mouse and rat preclinical models. Infusion of amylin (1 mg/kg/d) via SC osmotic minipumps for 7-21 days in mice decreased immobility in the forced swim test (FST). In contrast to known antidepressants, acute administration of amylin (IP or SC) had no effect in the mouse FST. In olfactory bulbectomized (OBX) rats a suppression of the OBX-induced hyperactivity was obtained as early as one day after amylin (0.3mg/kg/d) and imipramine (10mg/kg/d) infusion. One week after cessation of 14 days of amylin treatment, OBX-induced hyperactivity remained comparable to sham-operated animals, indicating long lasting effects of amylin. Chronic amylin effects on prefrontal cortex (PFC) monoaminergic transmission were then examined by in vivo microldialysis in mice. Unlike DOV-216,303 (a dopamine (DA), serotonin (5-HT), norepinephrine (NE) reuptake inhibitor), neither acute (10mg/kg) nor chronic amylin infusion (0.3, 1, and 3mg/kg/d) for 21 days increased DA, 5-HT, and NE level in the PFC indicating that antidepressant effects of amylin might be independent of monoamine release. Based on these results, PSN0041, a novel amylin mimetic petide, was identified after screening more than 200 amylin analogs through PsychoGenics proprietary in vivo drug discovery technologies. In mice, PSN0041 was more potent than amylin in reducing immobility in the FST (MED=0.03 vs 1 mg/kg/d, 7d infusion), and in decreasing the number of marbles in the marble burying (MRB) test (MED=0.3mg/kg vs 3mg/kg IP). PSN0041 was also optimized through SAR studies to increase duration of action. The effect of PSN0041 (3 mg/kg, IP) in the MRB test was sustained up to 4 hr compared to 30 min with amylin treatment (3 mg/kg, IP). Finally, in rats PSN0041 showed a clear superiority compared to known antidepressants; PSN0041 enhanced cognitive performance in the novel object recognition test, induced weight loss, and did not produce sexual dysfunction (0.1, 0.3, and 1mg/kg/d, 21d infusion). In conclusion, PSN0041 is a unique, first-in-class compound with enhanced pharmacological properties over native amylin and is anticipated to differentiate from current marketed antidepressants.