Exploration of the accessory binding region in the D1 dopamine receptor

Alia Huang Clark, Purdue University

Abstract

To gain a better understanding of the functional topography of the D 1 dopamine receptor accessory binding region, a series of ligands possessing a pendant phenyl substituent was synthesized and evaluated for their D 1-like and D2-like receptor affinities and functional activities. Conformational analysis of structurally-restricted analogs of SKF 38393 and ring-expanded analogs of doxthanrine demonstrated the importance of the orientation of the β-phenyl ring for receptor affinity and activity. The placement of the β-phenyl ring must be well defined with very little tolerance for conformational variability. In order to achieve high affinity and full agonist activity, the amine nitrogen should be positioned in the same plane as the catechol ring, with the β-phenyl substituent oriented slightly above and close to planarity with the catechol plane. To explore the accessory region beyond the β-phenyl ring binding site, compounds 9 and 10 with their pendant phenyl ring displaced two atoms from the β-position were synthesized. Molecular modeling of 9 and 10 not only identified potential residues in the accessory region that are crucial for ligand-receptor interactions, but also helped further define the boundary of this binding pocket. In addition, synthesis of 10 led to the development of a new class of potent, selective D2 agonist. SAR studies of 10 and its pendant ring-substituted analogs indicated the presence of an accessory ring binding site in the D 2 receptor, and provided preliminary data on the electronic properties of this region. Overall, these results have deepened our understanding of the D1 receptor binding site.

Degree

Ph.D.

Advisors

Nichols, Purdue University.

Subject Area

Biochemistry

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