title: Simplified tetrandrine congeners as possible antihypertensive agents with a dual mechanism of action.
abstract: A series of O- and/or N-substituted derivatives of (+/-)-coclaurine (1a) were synthesized as simplified structural mimics of the antihypertensive alkaloid tetrandrine (2) and assayed for binding to brain cortical sites labeled with the alpha(1)-adrenergic radioligand [(3)H]prazosin or the calcium channel radioligand [(3)H]diltiazem. The introduction of O-benzyl groups on the coclaurine molecule, which exhibits only adrenergic antagonist activity, led to the appearance of calcium channel blocking activity comparable to that of tetrandrine while retaining adrenolytic activity in the same concentration range. Contraction of aortal rings with noradrenaline or KCl was relaxed more potently by some of these coclaurine derivatives than by tetrandrine, suggesting leads for the development of novel antihypertensive drugs with a dual mechanism of action.
authors.affiliation: Millennium Institute for Advanced Research in Cell Biology and Biotechnology and Departamento de Química, Facultad de Ciencias, Universidad de Chile, Casilla 653, Santiago, Chile.
authors.forename: Patricio
authors.initials: P
authors.lastname: Iturriaga-Vásquez
authors.forename: Raquel
authors.initials: R
authors.lastname: Miquel
authors.forename: M Dolores
authors.initials: MD
authors.lastname: Ivorra
authors.forename: M Pilar
authors.initials: MP
authors.lastname: D'Ocon
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Cassels
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry*; D000959:Antihypertensive Agents; D044182:Benzylisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D004110:Diltiazem / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D008968:Molecular Conformation; D018716:Molecular Mimicry; D015394:Molecular Structure; D011224:Prazosin / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D000959:Antihypertensive Agents; D044182:Benzylisoquinolines; D002121:Calcium Channel Blockers; D007546:Isoquinolines; C009438:tetrandrine; C004690:coclaurine; D004110:Diltiazem; D011224:Prazosin