Synthesis and Biological Evaluation of 1, 2, 3, 4-Tetrahydroisoquinoline Derivatives as Potent and Selective M2 Muscarinic Receptor Antagonists

• Published in: Chemical & pharmaceutical bulletin Vol. 47; no. 5; pp. 672 - 677
• Main Authors: WATANABE, Toshihiro, KINOYAMA, Isao, TAKIZAWA, Kenji, HIRANO, Seiko, SHIBANUMA, Tadao
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 1999; Maruzen; Japan Science and Technology Agency
• Subjects: 1, 2, 3, 4-tetrahydroisoquinoline derivative; Animals; antagonism; Biological and medical sciences; bradycardia; Cardiovascular system; Heart Rate - drug effects; In Vitro Techniques; Isoquinolines - chemical synthesis; Isoquinolines - pharmacology; M2 muscarinic receptor; M2 selectivity; Male; Medical sciences; Membranes - drug effects; Membranes - metabolism; Miscellaneous; Muscarinic Antagonists - chemical synthesis; Muscarinic Antagonists - pharmacology; Neurotoxins - chemical synthesis; Neurotoxins - pharmacology; Pharmacology. Drug treatments; Rats; Rats, Wistar; Receptor, Muscarinic M2; Receptors, Muscarinic - drug effects; Structure-Activity Relationship; Submandibular Gland - drug effects; Tetrahydroisoquinolines; Intravenous administration; Rat; Arrhythmia; Nitrogen heterocycle; Lactam; Cardiovascular disease; Structure activity relation; Heart disease; Aromatic compound; Antagonist; Chemical synthesis; Isoquinoline derivatives; Rodentia; Aminoether; Tricyclic compound; In vitro; In vivo; Vertebrata; Bradycardia; Chemotherapy; Experimental disease; Mammalia; Treatment; Animal; M2 Muscarinic receptor; Carboxamide
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.47.672

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 lenght are crucially important for increased M2 affinity.