Pharmacological and behavioral properties of A-349821, a selective and potent human histamine H3 receptor antagonist

Histamine H-3 receptors regulate the release of a variety of central neurotransmitters involved in cognitive processes. A-349821 ((4'-(3((R,R)2,5-dimethyl-pyffolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone) is a novel, non-imidazole H-3 receptor ligand, displaying high affinity for recombinant rat and human H-3 receptors, with pK(i) values of 9.4 and 8.8, respectively, and high selectivity for the H-3 receptor versus H-1, H-2, and H-4 histamine receptors. A-349821 is a potent H-3 receptor antagonist in a variety of models using recombinant human and rat receptors, reversing agonist induced changes in cyclic AMP formation (pK(b) = 8.2 and pK(b) = 8. 1, respectively), [S-35]-GTPTS binding (pK(b) = 9.3 and pK(b) = 8.6, respectively) and calcium levels (human pK(b) = 8.3). In native systems, A-349821 competitively reversed agonist induced inhibition of electric field stimulated guinea-pig ileum (pA(2) = 9.5) and histamine-mediated inhibition of [H-3]-histamine release from rat brain cortical synaptosomes (pK(b) = 9.2). Additionally, A-349821 inhibited constitutive GTPgammaS binding at both rat and human H-3 receptors with respective pEC(50) values of 9.1 and 8.6, demonstrating potent inverse agonist properties. In behavioral studies, A-349821 (0.4 mg/kg-4 mg/kg) potently blocked (R)-alpha-methylhistamine-induced dipsogenia in mice. The compound also enhanced cognitive activity in a five-trial inhibitory avoidance model in spontaneously hypertensive rat (SHR) pups at doses of 1-10 mg/kg, with the 1 mg/kg dose showing comparable efficacy to a fully efficacious dose of ciproxifan (3 mg/ kg). These doses of A-349821 were without effect on spontaneous locomotor activity. Thus, A-349821 is a novel, selective non-imidazole H-3 antagonist/inverse agonist with balanced high potency across species and favorable cognition enhancing effects in rats. (C) 2004 Elsevier Inc. All rights reserved.