title: Synthesis and structure-activity relationships of new (5R,8R,10R)-ergoline derivatives with antihypertensive or dopaminergic activity.
abstract: 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.
authors.affiliation: Research Laboratories, Maruko Seiyaku Co., Ltd., Aichi, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ohno
authors.forename: Y
authors.initials: Y
authors.lastname: Adachi
authors.forename: M
authors.initials: M
authors.lastname: Koumori
authors.forename: K
authors.initials: K
authors.lastname: Mizukoshi
authors.forename: M
authors.initials: M
authors.lastname: Nagasaka
authors.forename: K
authors.initials: K
authors.lastname: Ichihara
authors.forename: E
authors.initials: E
authors.lastname: Kato
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects; D004285:Dogs; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D004873:Ergolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006439:Hemodynamics / Q000187:drug effects; D051379:Mice; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship
chemical_list: D000959:Antihypertensive Agents; D015259:Dopamine Agents; D004873:Ergolines