- Structure-Activity Relationships in the trans-Hexahydroindolophenanthridine ("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 Mode
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4,6,6a,7,8,12b-Hexahydroindolophenanthridines ("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 struct ure 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, Max P.,Floersheim, Philipp,Markstein, Rudolf,Widmer, Armin
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- trans-Hexahydroindolophenanthridines ("Benzergolines"), the First Structural Class of Potent and Selective Dopamine D1 Receptor Agonists Lacking a Catechol Group
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In contrast to the many selective dopamine (DA) D2 receptor agonists known, only two prototypes of selective D1 receptor agonists have been described; both show preference for the periphery due to their catechol partial structures.Ou
- Seiler, Max. P.,Hagenbach, Alexander,Wuethrich, Hans-Juerg,Markstein, Rudolf
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p. 303 - 307
(2007/10/02)
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- INDOLOPHENANTHRIDINES USEFUL AS DOPAMINERGIC AND ANALGESIC AGENTS
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4,6,6a,7,8,12b-hexahydro-indolo[4,3-ab]phenanthridines are useful as dopaminergic and analgesic agents.
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