Synthesis and Structure-Activity Relationships of New (5R, 8S, 10R)-Ergoline Derivatives with Antihypertensive or Dopaminergic Activity

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A series of new (5R, 8S, 10R)-ergoline derivatives was synthesized, and their antihypertensive and dopaminergic activities were evaluated in conscious spontaneously hypertensive rats and in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra, respectively. (5R, 8S, 10R)-6-Methyl-8-ergolinemethanols, prepared from the corresponding ergolinecarboxylates, were converted to the tosylates, which were treated with various five-membered heterocycles containing nitrogen atoms to afford the new ergolines. (5R, 8S, 10R)-8-(1-Imidazolylmethyl)-6-methylergoline (5a, BAM-2101) and (5R, 8S, 10R)-2-bromo-6-methyl-8-(1,2,4-triazol-1-ylmethyl)ergoline (7c, BAM-2202) exhibited potent antihypertensive activities. The maximum falls of systolic blood pressure after oral administration of 5a and 7c at 3mg/kg were 95 and 132 mmHg, respectively, while those of cianergoline, bromocriptine mesylate, hydralazine, and nifedipine at the same dose were 40,37,47,and 49 mmHg, respectively. The durations of significant antihypertensive effects of these compounds except nifedipine were more than 7h. None of the ergolines exhibited potent dopaminergic activity. Structure-activity relationships are discussed.
公益社団法人日本薬学会の論文
1994-10-15