title: Affinity profiles of BTM-1086 and BTM-1041 at muscarinic receptor subtypes and at H1- and alpha 1-receptors.
abstract: The affinities of the (+) and (-) enantiomers of the antimuscarinic benzothiazepinone derivative, cis-2,3-dihydro-3-(4-methyl-1-piperazinylmethyl)-2-phenyl-1,5-benzoth iazepin-4 (5H)-one (BTM-1041 and BTM-1086), for muscarinic receptor subtypes, histamine H1-receptors and alpha 1-adrenoceptors were determined in vitro using isolated organs: field-stimulated rabbit vas deferens (M1-receptors), guinea-pig left atrium (M2-receptors), guinea-pig ileum (M3- and histamine H1-receptors) and rat vas deferens (alpha 1-adrenoceptors). We also assessed the binding profile of BTM-1041 and BTM-1086 at muscarinic receptor subtypes in guinea-pig cortex (M1), heart (M2) and salivary glands (M3) as well as at alpha 1-adrenoceptors in rat cerebral cortex. Functional and binding experiments showed that the (-) enantiomer (BTM-1086) had a high affinity (pA2 = 7.98-8.81; pKi = 8.31-9.15) for the three muscarinic receptor subtypes, whereas the (+) enantiomer (BTM-1041) showed a low antimuscarinic potency (pA2 = 4.87-5.31; pKi = 4.85-5.55). This results in an extremely high stereoselectivity for these optical isomers [-)/(+) ratios = 1023 to 6918). The affinity of the (-) enantiomer BTM-1086 was lower for both histamine H1- and alpha 1-receptors than for muscarinic receptors, whereas the reverse was true for the (+) enantiomer, BTM-1041. Thus, the stereochemical demands for the two optical isomers were most stringent at muscarinic receptors but were inverse and less pronounced at histamine H1- and alpha 1-receptors (stereoselectivity ratios = 0.16-0.22).
authors.affiliation: Department of Pharmacology, Byk Gulden Pharmaceuticals, Konstanz, F.R.G.
authors.forename: M
authors.initials: M
authors.lastname: Eltze
authors.forename: R
authors.initials: R
authors.lastname: Boer
authors.forename: E
authors.initials: E
authors.lastname: Mutschler
authors.forename: G
authors.initials: G
authors.lastname: Lambrecht
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010276:Parasympatholytics / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism*; D013237:Stereoisomerism; D013841:Thiazepines / Q000378:metabolism*
chemical_list: D000317:Adrenergic alpha-Antagonists; D006634:Histamine H1 Antagonists; D010276:Parasympatholytics; D011942:Receptors, Adrenergic, alpha; D013841:Thiazepines; C029165:BTM 1042