Design and synthesis of novel α1a adrenoceptor-selective antagonists. 2. Approaches to eliminate opioid agonist metabolites via modification of linker and 4- …

…, D Nagarathnam, MR Marzabadi, B Lagu…

Index: Dhar, T. G. Murali; Nagarathnam, Dhanapalan; Marzabadi, Mohammad R.; Lagu, Bharat; Wong, Wai C.; Chiu, George; Tyagarajan, Sriram; Miao, Shou Wu; Zhang, Fengqi; Sun, Wanying; Tian, Dake; Shen, Quanrong; Zhang, Jack; Wetzel, John M.; Forray, Carlos; Chang, Raymond S. L.; Broten, Theodore P.; Schorn, Terry W.; Chen, Tsing Bao; O'Malley, Stacy; Ransom, Richard; Schneck, Kathryn; Bendesky, Robert; Harrell, Charles M.; Vyas, Kamlesh P.; Zhang, Kanyin; Gilbert, John; Pettibone, Douglas J.; Patane, Michael A.; Bock, Mark G.; Freidinger, Roger M.; Gluchowski, Charles Journal of Medicinal Chemistry, 1999 , vol. 42, # 23 p. 4778 - 4793

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Citation Number: 27

Abstract

We have previously described compound 1a as a high-affinity subtype selective α1a antagonist. In vitro and in vivo evaluation of compound 1a showed its major metabolite to be a μ-opioid agonist, 4-methoxycarbonyl-4-phenylpiperidine (3). Several dihydropyrimidinone analogues were synthesized with the goal of either minimizing the formation of 3 by modification of the linker or finding alternative piperidine moieties which when cleaved as ...