Conformational analysis and structure-activity relationships of selective dopamine D-1 receptor agonists and antagonists of the benzazepine series.
Comprehensive conformational analysis using molecular mechanics calculations (MM2(85)) has been carried out for the potent and selective dopamine D-1 receptor agonist 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1; SK&F 38393), the antagonist 7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (8; SCH 23390), and several analogues, including conformationally constrained ones. Calculated conformational energies have been related to pharmacological and biochemical data in an attempt to identify the biologically active conformations of 1 and 8. It is concluded that the most probable receptor-bound conformation in both cases is a chair conformation with an equatorial phenyl ring and for 8 an equatorial N-methyl group. It is suggested that the orientation of the phenyl ring in the receptor-bound molecule does not deviate in terms of dihedral angles by more than about 30 degrees from the preferred phenyl group rotamer in which the planes of two aromatic rings are essentially orthogonal.
Pettersson
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Department of Organic Chemistry, Royal Danish School of Pharmacy, Copenhagen, Denmark.
Liljefors
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T
Bøgesø
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D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D001552:Benzazepines; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D008968:Molecular Conformation; D015394:Molecular Structure; D011954:Receptors, Dopamine / Q000502:physiology*; D017447:Receptors, Dopamine D1; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D001552:Benzazepines; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine