Pharmacological characterization and appetite suppressive properties of BMS-193885, a novel and selective neuropeptide Y(1) receptor antagonist

Abstract

Treatment of obesity is still a large unmet medical need. Neuropeptide Y is the most potent orexigenic peptide in the animal kingdom. Its five cloned G-protein couple receptors are all implicated in the regulation of energy homeostasis evidenced by overexpression or deletion of neuropeptide Y or its receptors. Neuropeptide Y most likely exerts its orexigenic activity via the neuropeptide Y(1) and neuropeptide Y(5) receptors, although the involvement of the neuropeptide Y(2) and neuropeptide Y(4) receptors are also gaining importance. The lack of potent, selective, and brain penetrable pharmacologic agents at these receptors made our understanding of the modulation of food intake by neuropeptide Y-ergic agents elusive. BMS-193885 (1,4-dihydro-[3-[[[[3-[4-(3-methoxyphenyl)-1-piperidinyl]propyl]amino] carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester) is a potent and selective neuropeptide Y(1) receptor antagonist. BMS-193885 has 3.3 nM affinity at the neuropeptide Y(1) receptor, acting competitively at the neuropeptide Y binding site. BMS-193885 increased the K(d) of [(125)I]PeptideYY from 0.35 nM to 0.65 nM without changing the B(max) (0.16 pmol/mg of protein) in SK-N-MC cells that endogenously express the neuropeptide Y(1) receptor. It is also found to be a full antagonist with an apparent K(b) of 4.5 nM measured by reversal of forskolin (FK)-stimulated inhibition of cAMP production by neuropeptide Y. Pharmacological profiling showed that BMS-193885 has no appreciable affinity at the other neuropeptide Y receptors, and is also 200-fold less potent at the alpha(2) adrenergic receptor. Testing the compound in a panel of 70 G-protein coupled receptors and ion channels resulted in at least 200-fold or greater selectivity, with the exception of the sigma(1) receptor, where the selectivity was 100-fold. When administered intracerebroventricularly or directly into the paraventricular nucleus of the hypothalamus, it blocked neuropeptide Y-induced food intake in rats. Intraperitoneal administration of BMS-193885 (10 mg/kg) also reduced one-hour neuropeptide Y-induced food intake in satiated rats, as well as spontaneous overnight food consumption. Chronic administration of BMS-193885 (10 mg/kg) i.p. for 44 days significantly reduced food intake and the rate of body weight gain compared to vehicle treated control without developing tolerance or affecting water intake. These results provide supporting evidence that BMS-193885 reduces food intake and body weight via inhibition of the central neuropeptide Y(1) receptor. BMS-193885 has no significant effect of locomotor activity up to 20 mg/kg dose after 1 h of treatment. It also showed no activity in the elevated plus maze when tested after i.p. and i.c.v. administration, indicating that reduction of food intake is unrelated to anxious behavior. BMS-193885 has good systemic bioavailability and brain penetration, but lacks oral bioavailability. The compound had no serious cardiovascular adverse effect in rats and dogs up to 30 and 10 mg/kg dose, respectively, when dosed intravenously. These data demonstrate that BMS-193885 is a potent, selective, brain penetrant Y(1) receptor antagonist that reduces food intake and body weight in animal models of obesity both after acute and chronic administration. Taken together the data suggest that a potent and selective neuropeptide Y(1) receptor antagonist might be an efficacious treatment for obesity in humans.