Inquiry into the structural and conformational requirements of beta-phenyldopamine-type ligands for selective dopamine D1 receptor activation

Juan Pablo Cueva, Purdue University

Abstract

To gain a better understanding of the structural and conformational features that enable selective activation of the dopamine D1 receptor by β-phenyldopamine-type ligands, a series of compounds was prepared and tested for their D1- and D2-like receptor affinities and for their ability to induce receptor activation. A new synthesis of the known D1-selective ligand dihydrexidine has been developed and modified to allow preparation of substituted hexahydrobenzo[a]phenanthridines. This novel approach allowed the synthesis of dihydrexidine analogs substituted with methyl groups on the 7-position, leading to the discovery that the D 1 and D2 receptors have no tolerance for substitutions in this region of the ligand. Replacement of the 8-methylene of dihydrexidine with an oxygen atom led to a new molecule that had dramatically increased selectivity and which was named doxanthrine. Extension of the SAR of these novel chromanoisoquinolines by substitutions on the β-phenyl ring revealed key differences between the interaction of this template and the hexahydrobenzo[ a]phenanthridines with the D1 receptor binding site. Investigation of the preferred conformation of the β-phenyl ring was carried out by examining the D1 receptor affinities of a ring-expanded analog of doxanthrine and a rigid analog of SKF38393, suggesting that deviation from coplanarity of this substituent appears to be necessary to achieve high affinity D1 binding. Overall, these studies have led to further improvements in our understanding of the functional topography of the dopamine D1 receptor.

Degree

Ph.D.

Advisors

Nichols, Purdue University.

Subject Area

Pharmacy sciences

COinS