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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National Institute of Mental Health (NIMH)
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Purdue University
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West Lafayette
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Clark, Alia H; McCorvy, John D; Conley, Jason M et al. (2012) Identification of a 2-phenyl-substituted octahydrobenzo[f]quinoline as a dopamine Dýýý receptor-selective full agonist ligand. Bioorg Med Chem 20:6366-74
Chemel, Benjamin R; Bonner, Lisa A; Watts, Val J et al. (2012) Ligand-specific roles for transmembrane 5 serine residues in the binding and efficacy of dopamine D(1) receptor catechol agonists. Mol Pharmacol 81:729-38
Cueva, Juan Pablo; Chemel, Benjamin R; Juncosa Jr, Jose I et al. (2012) Analogues of doxanthrine reveal differences between the dopamine D1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridines. Eur J Med Chem 48:97-107
Cueva, Juan Pablo; Gallardo-Godoy, Alejandra; Juncosa, Jose I et al. (2011) Probing the steric space at the floor of the D1 dopamine receptor orthosteric binding domain: 7ýý-, 7ýý-, 8ýý-, and 8ýý-methyl substituted dihydrexidine analogues. J Med Chem 54:5508-21
Clark, Alia H; McCorvy, John D; Watts, Val J et al. (2011) Assessment of dopamine Dýýý receptor affinity and efficacy of three tetracyclic conformationally-restricted analogs of SKF38393. Bioorg Med Chem 19:5420-31
Bonner, Lisa A; Laban, Uros; Chemel, Benjamin R et al. (2011) Mapping the catechol binding site in dopamine D? receptors: synthesis and evaluation of two parallel series of bicyclic dopamine analogues. ChemMedChem 6:1024-40
Bonner, Lisa A; Chemel, Benjamin R; Watts, Val J et al. (2010) Facile synthesis of octahydrobenzo[h]isoquinolines: novel and highly potent D1 dopamine agonists. Bioorg Med Chem 18:6763-70
Przybyla, Julie A; Cueva, Juan P; Chemel, Benjamin R et al. (2009) Comparison of the enantiomers of (+/-)-doxanthrine, a high efficacy full dopamine D(1) receptor agonist, and a reversal of enantioselectivity at D(1) versus alpha(2C) adrenergic receptors. Eur Neuropsychopharmacol 19:138-46
Cueva, Juan Pablo; Giorgioni, Gianfabio; Grubbs, Russell A et al. (2006) trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline: synthesis, resolution, and preliminary pharmacological characterization of a new dopamine D1 receptor full agonist. J Med Chem 49:6848-57
Ryman-Rasmussen, Jessica P; Nichols, David E; Mailman, Richard B (2005) Differential activation of adenylate cyclase and receptor internalization by novel dopamine D1 receptor agonists. Mol Pharmacol 68:1039-48

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