Synthesis and Biological Evaluation of 1, 2, 3, 4-Tetrahydroisoquinoline Derivatives as Potent and Selective M2 Muscarinic Receptor Antagonists
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...
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Published in | Chemical & pharmaceutical bulletin Vol. 47; no. 5; pp. 672 - 677 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Tokyo
The Pharmaceutical Society of Japan
1999
Maruzen Japan Science and Technology Agency |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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ISSN: | 0009-2363 1347-5223 |
DOI: | 10.1248/cpb.47.672 |