title: Cardiovascular effects of CP-96,345, a non-peptide blocker of tachykinin NK1 receptors.
abstract: CP-96,345, a non-peptide, selective tachykinin NK1 receptor blocker and its inactive enantiomer, CP-96,344, inhibit ligand binding of phenylalkylamine but not dihydropyridine Ca2+ channel antagonists. Whether these Ca2+ channel antagonist properties of CP-96,345 and CP-96,344 can be expressed as cardiovascular effects in vitro and in vivo is unknown. The cardiovascular effects of CP-96,345 and CP-96,344 in isolated vascular smooth muscle and in anesthetized dogs were compared to those of verapamil and nifedipine, phenylalkylamine and dihydropyridine Ca2+ channel antagonists, respectively. CP-96,345, CP-96,344, verapamil and nifedipine inhibited Ca(2+)-induced contractions in rat isolated portal vein with pD2' values of 5.9, 5.8, 6.8 and 8.1, respectively. In closed chest, anesthetized, spinal-pithed dogs, CP-96,345 caused dose-related hypotension and depressed heart rate. In open chest, anesthetized beagles at equihypotensive doses, CP-96,345, 1 mg/kg, CP-96,344, 1 mg/kg and verapamil, 0.5 mg/kg caused significant negative chronotropic, dromotropic and inotropic effects that were not observed with nifedipine, 0.01 mg/kg or nitroglycerin, 0.02 mg/kg. We conclude that the cardiovascular effects of CP-96,345 and its isomer are due to 'verapamil-like' Ca2+ channel antagonism and are not related to blockade of NK1 receptors.
authors.affiliation: Department of Exploratory Medicinal Chemistry, Pfizer Inc., Groton, CT 06340.
authors.forename: J W
authors.initials: JW
authors.lastname: Constantine
authors.forename: W S
authors.initials: WS
authors.lastname: Lebel
authors.forename: H A
authors.initials: HA
authors.lastname: Woody
authors.forename: P A
authors.initials: PA
authors.lastname: Benoit
authors.forename: E A
authors.initials: EA
authors.lastname: Wolfgang
authors.forename: D R
authors.initials: DR
authors.lastname: Knight
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D064729:Neurokinin-1 Receptor Antagonists; D011169:Portal Vein / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers; D064729:Neurokinin-1 Receptor Antagonists; D002118:Calcium; C066892:CP 96345