Structure-activity relationships in the trans-hexahydroindolo[4,3-ab]phenanthridine ("benzergoline") series. 2. Resolution, absolute configuration, and dopaminergic activity of the selective D1 agonist CY 208-243 and its implication for an "extended rotamer-based dopamine receptor model".
4,6,6a,7,8,12b-Hexahydroindolo[4,3-ab]phenanthridines ("benzergolines") was the first structural class of potent and selective dopamine D1 agonists lacking a catechol group. In order to determine the enantioselectivity of the 7-methyl derivative in the adenylate cyclase assay, its 5,5a-dihydro precursor was resolved and both enantiomers oxidized to the final products. The biological activity was found to reside entirely in the (-)-enantiomer, (-)-1 (CY 208-243). An X-ray study of its (-)-mandelic acid salt revealed a 6aR,12bR absolute configuration, which, in confirmation of the structure hypothesis, corresponds to that of the ergolines. Unexpectedly, an axial conformation of the N-methyl group was observed in the crystal structure. In contrast, subsequently analyzed crystals of the free base of (-)-1 revealed an equatorial conformation of the N-methyl group, which, we assume, represents the bioactive conformation. Based on the determined absolute configuration, (-)-1 could be oriented in a previously described "rotamer-based dopamine receptor model", which allowed the localization of a "subtype selectivity-inducing site" (aryl binding site at the D1 receptor, steric barrier at the D2 receptor), marked by the conformationally fixed "additional" phenyl group of the benzergoline molecule.
Seiler
M P
MP
Sandoz Pharma Ltd., Preclinical Research, Basel, Switzerland.
Floersheim
P
P
Markstein
R
R
Widmer
A
A
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D015259:Dopamine Agents / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D010617:Phenanthridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D015259:Dopamine Agents; D007211:Indoles; D010617:Phenanthridines; C054531:CY 208-243; D000262:Adenylyl Cyclases