SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF NEW (5R,8R,10R)-ERGOLINE DERIVATIVES WITH ANTIHYPERTENSIVE OR DOPAMINERGIC ACTIVITY

A series of new (5R,8R,10R)-ergoline derivatives was synthesized, and their antihypertensive and dopaminergic activities were tested in cons cious spontaneously hypertensive rats and in rats with unilateral 6-hy droxydopamine-induced lesions of the substantia nigra. (5R,8R,10R)-6-A lkyl-8-ergolinemethanols, prepared from the corresponding ergolinecarb oxylates, were converted to the tosylates, which were treated with var ious five-membered heterocycles containing nitrogen atoms to afford th e new ergolines. 10R)-8-(1,2,4-Triazol-1-ylmethyl)-6-methylergoline (4 s, maleate: BAM-1110) exhibited potent dopaminergic activity, about 18 -fold greater than that of bromocriptine mesylate. 10R)-8-(1,2,4-Triaz ol-1-ylmethyl)-6-propylergoline (8b, fumarate: BAM-1602) showed extrem ely potent dopaminergic activity, being about 220 and 1.15 times more active than bromocriptine mesylate and pergolide mesylate, respectivel y. Several compounds exhibited potent antihypertensive activity. Struc ture-activity relationships for antihypertensive and dopaminergic acti vities are discussed.