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

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A series of new (5R, 8R, 10R)-ergoline derivatives was synthesized, and their antihypertensive and dopaminergic activities were tested in conscious spontaneously hypertensive rats and in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra. (5R, 8R, 10R)-6-Alkyl-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, 8R, 10R)-8-(1,2,4-Triazol-1-ylmethyl)-6-methylergoline (4s, maleate : BAM-1110) exhibited potent dopaminergic activity, about 18-fold greater than that of bromocriptine mesylate. (5R, 8R, 10R)-8-(1,2,4-Triazol-1-ylmethyl)-6-propylergoline (8b, fumarate : BAM-1602) showed extremely potent dopaminergic activity, being about 220 and 1.15 times more active than bromocriptine mesylate and pergolide mesylate, respectively. Several compounds exhibited potent antihypertensive activity. Structure-activity relationships for antihypertensive and dopaminergic activities are discussed.
公益社団法人日本薬学会の論文
1994-07-15