Simplified tetrandrine congeners as possible antihypertensive agents with a dual mechanism of action.
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.
Iturriaga-Vásquez
Patricio
P
Millennium Institute for Advanced Research in Cell Biology and Biotechnology and Departamento de Química, Facultad de Ciencias, Universidad de Chile, Casilla 653, Santiago, Chile.
Miquel
Raquel
R
Ivorra
M Dolores
MD
D'Ocon
M Pilar
MP
Cassels
Bruce K
BK
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
D000470:Alkaloids; D000959:Antihypertensive Agents; D044182:Benzylisoquinolines; D002121:Calcium Channel Blockers; D007546:Isoquinolines; C009438:tetrandrine; C004690:coclaurine; D004110:Diltiazem; D011224:Prazosin