title: Pharmacological characterization of A-960656, a histamine H₃ receptor antagonist with efficacy in animal models of osteoarthritis and neuropathic pain.
abstract: Histamine H(3) receptor antagonists have been widely reported to improve performance in preclinical models of cognition, but more recently efficacy in pain models has also been described. Here, A-960656 ((R)-2-(2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-yl)pyridazin-3(2H)-one) was profiled as a new structural chemotype. A-960656 was potent in vitro in histamine H(3) receptor binding assays (rat K(i)=76 nM, human K(i)=21 nM), and exhibited functional antagonism in blocking agonist-induced [(35)S]GTPγS binding (rat H(3) K(b)=107 nM, human H(3) K(b)=22 nM), and was highly specific for H(3) receptors in broad screens for non-H(3) sites. In a spinal nerve ligation model of neuropathic pain in rat, oral doses of 1 and 3mg/kg were effective 60 min post dosing with an ED(50) of 2.17 mg/kg and a blood EC(50) of 639 ng/ml. In a model of osteoarthritis pain, oral doses of 0.1, 0.3, and 1mg/kg were effective 1h post dosing with an ED(50) of 0.52 mg/kg and a blood EC(50) of 233 ng/ml. The antinociceptive effect of A-960656 in both pain models was maintained after sub-chronic dosing up to 12 days. A-960656 had excellent rat pharmacokinetics (t(1/2)=1.9h, 84% oral bioavailability) with rapid and efficient brain penetration, and was well tolerated in CNS behavioral safety screens. In summary, A-960656 has properties well suited to probe the pharmacology of histamine H(3) receptors in pain. Its potency and efficacy in animal pain models provide support to the notion that histamine H(3) receptor antagonists are effective in attenuating nociceptive processes.
authors.affiliation: Department of Neuroscience Research, Abbott Laboratories, Abbott Park, IL 60064, United States. marlon.d.cowart@abbott.com
authors.forename: Marlon
authors.initials: M
authors.lastname: Cowart
authors.forename: Gin
authors.initials: G
authors.lastname: Hsieh
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Black
authors.forename: Cenchen
authors.initials: C
authors.lastname: Zhan
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Gomez
authors.forename: Madhavi
authors.initials: M
authors.lastname: Pai
authors.forename: Marina
authors.initials: M
authors.lastname: Strakhova
authors.forename: Arlene
authors.initials: A
authors.lastname: Manelli
authors.forename: Tracy
authors.initials: T
authors.lastname: Carr
authors.forename: Jill
authors.initials: J
authors.lastname: Wetter
authors.forename: Anthony
authors.initials: A
authors.lastname: Lee
authors.forename: Gilbert
authors.initials: G
authors.lastname: Diaz
authors.forename: Tiffany
authors.initials: T
authors.lastname: Garrison
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Brioni
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D065607:Cytochrome P-450 Enzyme Inhibitors; D004195:Disease Models, Animal; D004285:Dogs; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D057809:HEK293 Cells; D006321:Heart / Q000187:drug effects; D054828:Histamine H3 Antagonists / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009437:Neuralgia / Q000188:drug therapy*; D010003:Osteoarthritis / Q000188:drug therapy*; D020370:Osteoarthritis, Knee / Q000188:drug therapy; D011724:Pyridazines / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: C574779:A-960656; D052160:Benzothiazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D054828:Histamine H3 Antagonists; D011724:Pyridazines; D018100:Receptors, Histamine H3