Chemical & Pharmaceutical Bulletin 2011-01-01

Synthesis and pharmacological evaluation of 1-isopropyl-1,2,3,4-tetrahydroisoquinoline derivatives as novel antihypertensive agents.

Susumu Watanuki, Keisuke Matsuura, Yuichi Tomura, Minoru Okada, Toshio Okazaki, Mitsuaki Ohta, Shin-Ichi Tsukamoto

Index: Chem. Pharm. Bull. 59(8) , 1029-37, (2011)

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Abstract

A series of 1-isopropyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized and their bradycardic activities were evaluated in isolated guinea pig right atria. Structure-activity relationship studies revealed that the introduction of an appropriate substituent and its position on the 1,2,3,4-tetrahydroisoquinoline ring are essential for potent in vitro activity. Furthermore, the tether between the piperidyl moiety and the terminal aromatic ring is important for potent antihypertensive activity. Oral administration of 6-fluoro-1-isopropyl-2-{[1-(2-phenylethyl)piperidin-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline (3b) to spontaneously hypertensive rats (SHR) elicited antihypertensive effects without inducing reflex tachycardia, which is often caused by traditional L-type Ca²⁺ channel blockers.