Our hypothesis that a beta-phenyldopamine moiety could serve as a dopamine D1 receptor pharmacophore has received strong support by our finding that (+)-trans-10,11-dihydroxy-hexahydrobenzo[a]phenanthridine (dihydrexidine) is a potent and selective dopamine D1 full agonist. Based on the near coplanarity of the two aromatic rings in dihydrexidine, we hypothesize that full efficacy agonists must be able to adopt a similar conformation, while for antagonists, the two rings may reside more skewed with respect to each other. The present proposal presents, for synthesis and pharmacological evaluation, an extensive series of conformationally-defined novel tetracyclic molecules designed around the beta-phenyldopamine template. Low energy conformations of the various molecules present the two aromatic rings of the pharmacophore in a variety of relative orientations, and the ethylamine fragment of the dopamine moiety in several conformations. The molecular fragments used to tither the pharmacophore are placed in several different locations, and the N-alkyl substituents will also be varied. Pharmacological evaluation, initially using in vitro methods, and later in vivo assays for interesting compounds, will focus on dopamine D1/D2 receptor selectivity, agonist versus antagonist activity, and for agonists, whether or not they are full efficacy. The biological data will then be considered in the context of conformational and steric properties of the molecules. Proprietary software routines, as embodied SYBYL and CHARMm will be used for energy minimization, and generation of receptor essential and receptor excluded volumes. It is anticipated that, with the range of molecules proposed for study, very well-defined conceptual models of the dopamine D1 receptor can be developed. These may encompass differing requirements for agonist versus antagonist binding, and may allow similarities and differences between the D1 and D2 receptors to be more clearly defined.
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