Expanding the structure-activity relationships of dopamine D1 agonists: Mapping the catechol hydrogen bonding network and probing the accessory binding region of D1 receptors
In a continued effort to fully understand the structural requirements of a D1-like-selective dopamine agonist, several series of non-β-phenyl-containing compounds were synthesized and evaluated for their ability to bind to and activate dopamine receptors. By comparing a newly synthesized carbocyclic series of bicyclic dopamine analogues to previously reported parallel isochroman and chroman series, we were able to discover significant information on the complex hydrogen bonding network present in the D1-like receptors. With the help of an in silico-activated D1 receptor model, we mapped this network and proposed structural requirements for a non-catechol D1-selective agonist. The synthesis of a previously unreported rigid dopamine scaffold led to the development of a potent, selective full D1 agonist, and inspired our examination of the potential for intramolecular hydrogen bonds to affect a ligand's affinity. Although we were unable to synthesize a D1- or D5-selective ligand, we extended the D1-like pharmacophore further into the accessory binding region of the receptor. The results presented here expand our knowledge of the nature of the D1 receptor binding pocket.
Nichols, Purdue University.
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