Exploring the molecular determinants of binding selectivity and efficacy for D1 dopamine receptor agonists

Benjamin Reed Chemel, Purdue University

Abstract

The D1 dopamine receptor is enriched in many areas of the brain and plays many important roles in the central nervous system. The involvement of these receptors in diverse processes, including the initiation of voluntary movement, learning and memory, as well as reinforcement and reward, suggest that they are important targets for the treatment of Parkinson’s disease, cognitive deficits, schizophrenia, and addiction, among others. To further our ongoing efforts to develop novel D1 receptor selective agonists, we employed a mutagenesis-based approach to investigate the molecular interactions between agonists and the ligand binding site of D1 receptors. Using binding and functional assays to examine the pharmacological effects of mutating key receptor amino acids on a number of structurally and pharmacologically distinct agonists, we were able to elucidate many structural features of the receptor and its ligands that define agonist binding and efficacy. Mutation of Ser198(5.42), Ser199(5.43) and Ser202(5.46) to alanine produced different patterns of effects on the pharmacologies of different structural classes of agonists, which were largely determined by the geometric constraints of the dopamine pharmacophore. These studies suggest that simultaneous engagement of Ser198 or Ser199 and Ser202 by the m-OH and p -OH of catechol ligands, respectively, is a requisite for high efficacy. Mutation of Ser107(3.36) to cysteine or valine and Thr108(3.37) to alanine resulted in highly variable changes in agonist affinity, potency, and efficacy that were not clearly related to ligand structural features. Ergoline agonists were uniquely affected by these six mutations, suggesting that these non-catechol agonists interact with D1 receptors in unique and potentially dynamic ways. Mutation of Phe313(7.35) to tyrosine or leucine demonstrated that this residue forms part of the “phenyl accessory region” and helps to mediate the D1 receptor selectivity possessed by the β-phenyl dopamine pharmacophore. By providing a unique understanding of the molecular interactions between agonists and D1 receptor binding domains, these studies help to refine the D1 agonist pharmacophore and may suggest new ways to design synthetic agonists that possess high efficacy and selectivity for D1 receptors.

Degree

Ph.D.

Advisors

Watts, Purdue University.

Subject Area

Neurosciences|Pharmacology|Pharmacy sciences

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