Journal of Medicinal Chemistry p. 1941 - 1946 (1988)
Update date:2022-09-26
Topics:
Charifson
Wyrick
Hoffman
Ademe Simmons
Bowen
McDougald
Mailman
A series of 1-phenyl-, 4-phenyl-, and 1-benzyl-1,2,3,4-tetrahydroisoquinolines have been prepared as ring-contracted analogues of the prototypical D1 dopamine receptor antagonist SCH23390 [(R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3 benzazepine]. The affinity and selectivity of these isoquinolines for D1 receptors was determined by three biochemical endpoints in membrane homogenates prepared from rat corpus striatum: the potency to compete for [3H]SCH23390 binding sites; the potency to compete for [3H]spiperone (a D2 receptor ligand) binding sites; and effects on dopamine-stimulated adenylate cyclase. Competitive binding measurements at D1 sites showed SCH23390 to possess the highest affinity, followed by 1-phenyl > 1-benzyl > 4-phenyl for the isoquinolines. These results were highly correlated with the ability of the test compounds to antagonize dopamine-stimulated adenylate cyclase (r = 0.98). None of the compounds alone stimulated cAMP formation at concentrations of 10 nM to 100 μM. D2 competition binding showed the 1-benzyl derivative to possess the highest affinity, followed by 4-phenyl > SCH23390 > 1-phenyl. The tertiary 1-phenyl derivative was more potent than the secondary 1-phenyl analogue in all assays. Interestingly, resolution and single-crystal X-ray analysis of the tertiary N-methyl-1-phenyltetrahydroisoquinoline showed the most active enantiomer to possess the S absolute configuration, in contrast to the benzazepine (R)-SCH23390.
View MoreShaanxi Lighte Optoelectronics Material Co., Ltd.
Contact:+86-29-88320728-622/619/620
Address:No.55 INDUSTRY ROAD 2,XI'AN NATIONAL CIVIL AEROSPACE INDUSTRIAL PARK.XI'AN China 710065.
Wuhan Kemi-Works Chemical Co., Ltd
website:http://www.kemiworks.com
Contact:86-27-85736489
Address:Rm. 1503, No. 164, Jianghan North Rd., Wuhan, 430022 China
Laizhou City Laiyu Chemical CO.,Ltd
Contact:+86-535-2719337/2719339
Address:Chenggang road zhuyou laizhou City Shangdong China
Wuhan ZeShanCheng Biomedical Technology Co., Ltd.
website:http://www.whzscsw.com/
Contact:+86 17786425391
Address:No. 399, lihua road, dongxihu district, wuhan city (17)
Hangzhou Hysen Pharma co.,Ltd.
website:http://www.hysenpharma.cn/
Contact:0086-571-88298791
Address:#701,Gudun Road Hangzhou
Doi:10.1016/j.bmc.2008.10.084
(2009)Doi:10.1248/cpb.38.2357
(1990)Doi:10.1016/0008-6215(88)84046-1
(1988)Doi:10.1055/s-0030-1258382
(2011)Doi:10.1055/s-0029-1216948
(2009)Doi:10.1021/acs.joc.0c01700
(2020)