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

A series of new (5R,8S,10R)-ergoline derivatives was synthesized, and their antihypertensive and dopaminergic activities were evaluated in c onscious 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 correspon ding ergolinecarboxylates, were converted to the tosylates, which were treated with various five-membered heterocycles containing nitrogen a toms to afford the new ergolines. 5R,8S,10R)-8-(1-Imidazolylmethyl)-6- methylergoline (5a, BAM-2101) and romo-6-methyl-8-(1,2,4-triazol-1-ylm ethyl)ergoline (7c, BAM-2202) exhibited potent antihypertensive activi ties. The maximum falls of systolic blood pressure after oral administ ration of 5a and 7c at 3 mg/kg were 95 and 132 mmHg, respectively, whi le those of cianergoline, bromocriptine mesylate, hydralazine, and nif edipine at the same dose were 40, 37, 47, and 49 mmHg, respectively. T he durations of significant antihypertensive effects of these compound s except nifedipine were more than 7 h. None of the ergolines exhibite d potent dopaminergic activity. Structure-activity relationships are d iscussed.