Conformational analysis and structure-activity relationships of selective dopamine D-1 receptor agonists and antagonists of the benzazepine series.

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Pettersson I, Liljefors T, Bogeso K

Conformational analysis and structure-activity relationships of selective dopamine D-1 receptor agonists and antagonists of the benzazepine series.

J Med Chem. 1990 Aug;33(8):2197-204.

PubMed ID

1973733 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Dopamine	Dopamine D1 receptor	Ki (nM)	192	N/A	N/A	Details