title: Characterization of BIBN 99: a lipophilic and selective muscarinic M2 receptor antagonist.
abstract: The present study was designed to characterize the receptor selectivity profile of the novel muscarinic M2 receptor antagonist BIBN 99 (5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1- oxopentyl)ethylamino]propyl]-1-piperidinyl]acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one). In radioligand binding studies BIBN 99 showed high affinity for m2/M2 sites (pKi = 7.52/7.57), intermediate affinity for m4 sites (pKi = 6.76) and low affinity for m1/M1 (pKi = 5.97/6.17), m3/M3 (pKi = 6.11/6.04) and m5 sites (pKi = 5.84). Functional studies in vitro showed BIBN 99 to be a competitive antagonist and to have an 11- to 25-fold higher affinity for M2 receptors than for putative M1 receptors in the rabbit vas deferens or M3 receptors in guinea-pig trachea. In vivo studies revealed that BIBN 99 is able to cross the blood-brain barrier, and although showing an approximately 3-fold higher affinity for M2 binding sites BIBN 99 appeared to be 7- to 18-fold less potent than AF-DX 116 in inhibiting muscarinic agonist or vagally induced bradycardia in rats and guinea-pigs. The results show that BIBN 99 is the first lipophilic muscarinic M2 receptor antagonist to have remarkable M2 versus M1 selectivity (30-fold). In addition, BIBN 99 possesses central nervous system activity and only minor peripheral cardiac effects.
authors.affiliation: Department of Pharma Research, Dr. Karl Thomae GmbH, Biberach, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Doods
authors.forename: M
authors.initials: M
authors.lastname: Entzeroth
authors.forename: H
authors.initials: H
authors.lastname: Ziegler
authors.forename: G
authors.initials: G
authors.lastname: Schiavi
authors.forename: W
authors.initials: W
authors.lastname: Engel
authors.forename: G
authors.initials: G
authors.lastname: Mihm
authors.forename: K
authors.initials: K
authors.lastname: Rudolf
authors.forename: W
authors.initials: W
authors.lastname: Eberlein
mesh_terms: D000818:Animals; D001665:Binding Sites; D003984:Dibenzazepines / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D018727:Muscarinic Antagonists; D009130:Muscle, Smooth / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010276:Parasympatholytics / Q000378:metabolism / Q000494:pharmacology*; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000378:metabolism
chemical_list: D003984:Dibenzazepines; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D011725:Pyridines; D011976:Receptors, Muscarinic; C079888:BIBN 99; D010890:Pirenzepine; C048593:otenzepad