title: Synthesis and pharmacological evaluation of 1-oxo-2-(3-piperidyl)-1,2,3,4- tetrahydroisoquinolines and related analogues as a new class of specific bradycardic agents possessing I(f) channel inhibitory activity.
abstract: A series of 1-oxo-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines and related analogues were prepared and evaluated for their bradycardic activities in isolated right atrium and in anesthetized rats. (+/-)-6,7-Dimethoxy-2-[1-[3-(3,4-methylenedioxyphenoxy)propyl]-3-piperidyl]-1,2,3,4-tetrahydroisoquinoline (4) was chosen as a lead, and structural modifications were performed on the tetrahydroisoquinoline ring and the terminal aromatic ring. The modifications on the tetrahydroisoquinoline ring revealed that the 1-oxo-1,2,3,4-tetrahydroisoquinoline ring system was optimum structure for both in vitro potency and in vivo efficacy. Furthermore, methoxy, ethoxy, and methoxycarbonyl groups were identified as preferable substituents on the terminal aromatic ring. One of the 1-oxo-1,2,3,4-tetrahydroisoquinoline derivatives, (R)-10a, was further evaluated for its bradycardic activity and inhibitory activity against I(f) currents. Compound (R)-10a demonstrated potent bradycardic activity in rats with minimal influence on blood pressure after oral administration. The compound also showed inhibition of I(f) currents (IC(50) = 0.32 muM) in guinea pig pacemaker cells.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kubota
authors.forename: Akio
authors.initials: A
authors.lastname: Kakefuda
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Watanabe
authors.forename: Noe
authors.initials: N
authors.lastname: Ishii
authors.forename: Koichi
authors.initials: K
authors.lastname: Wada
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Masuda
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tsukamoto
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003864:Depression, Chemical; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects* / Q000502:physiology; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012849:Sinoatrial Node / Q000166:cytology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C478624:6,7-dimethoxy-2-(1-(3-(3,4-methylenedioxyphenoxy)propyl)-3-piperidyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; D007473:Ion Channels; D007546:Isoquinolines; D010880:Piperidines