title: Synthesis and biological evaluation of 1,2,3,4-tetrahydroisoquinoline derivatives as potent and selective M2 muscarinic receptor antagonists.
abstract: A series of 1,2,3,4-tetrahydroisoquinoline derivatives containing the 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one skeleton were prepared and evaluated for their in vitro binding affinities to muscarinic receptors and for antagonism of bradycardia in vivo. Among them, compound 3f had the highest affinity for M2 muscarinic receptors in the heart (pKi = 9.1) with low affinity for M3 muscarinic receptors in the submandibular gland. A structure-activity relationship (SAR) study suggested that the benzene ring fused piperidine and the alkyl linker chain length are crucially important for increased M2 affinity.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: I
authors.initials: I
authors.lastname: Kinoyama
authors.forename: K
authors.initials: K
authors.lastname: Takizawa
authors.forename: S
authors.initials: S
authors.lastname: Hirano
authors.forename: T
authors.initials: T
authors.lastname: Shibanuma
mesh_terms: D000818:Animals; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D009498:Neurotoxins / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013363:Submandibular Gland / Q000187:drug effects; D044005:Tetrahydroisoquinolines
chemical_list: D007546:Isoquinolines; D018727:Muscarinic Antagonists; D009498:Neurotoxins; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline