title: Synthesis and pharmacological evaluation of 1-isopropyl-1,2,3,4-tetrahydroisoquinoline derivatives as novel antihypertensive agents.
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.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Japan. susumu.watanuki@jp.astellas.com
authors.forename: Susumu
authors.initials: S
authors.lastname: Watanuki
authors.forename: Keisuke
authors.initials: K
authors.lastname: Matsuura
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tomura
authors.forename: Minoru
authors.initials: M
authors.lastname: Okada
authors.forename: Toshio
authors.initials: T
authors.lastname: Okazaki
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Tsukamoto
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D020747:Calcium Channels, T-Type / Q000378:metabolism; D006168:Guinea Pigs; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use*
chemical_list: D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline