We have proposed that molecules containing a """"""""beta-phenyldopamine"""""""" moiety are specific D-1 and DA1 dopamine agonists. SKF 38393 and 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline are representative of this class. SCH 3390, a specific D-I antagonist also contains a beta-phenyl-2-phenethylamine fragment. A variety of conformationally defined novel structures containing his element will be synthesized and evaluated for D-I and D-2 dopamine agonist and antagonist activity. Principal structural types to be assessed are mono nd dihydroxy-, and monohydroxy-bromo substituted trans-5,6,6a,7,9,12b-hexaydrobenzo(a)phenanthridines, and dibenzo(a,d)1,4-cycloheptadiene, and 9,10-dihydroanthracene derivatives. The racemic materials will be pharmacologically characterized, and all compounds with significant biological activity will be resolved and the absolute configuration of the more active enantiomer will be determined by x-ray crystallography. Structure-activity relationships will be developed for these classes, and attempts will be made to develop a three-dimensional topographical model of the dopamine D-1 receptor.
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