Based upon the results of our previous structure activity relationship studies, we have developed a hypothesis to explain the interaction of DAergic agonist and antagonist drugs with DAergic receptors. We have consistently found that permanently charged dopamine agonist and antagonist molecules, while capable of binding to dopamine receptors, have a lower affinity for D2 and D1 dopamine receptors than parent amines which can exist in both protonated (charged) and unprotonated (uncharged) forms at physiological pH. To explain these differences in potency, we propose that: DAergic agonist and antagonists bind to a carboxylate site on the receptor. Thus, the permanently charged analogs would bind to this anionic site. However, the parent agonist and antagonist amines in the protonated form can bind to the receptor in an additional manner: by hydrogen bonding. This hydrogen bonding would reinforce the ionic bond resulting in a stronger bond between the receptor and the drug than the ionic bond alone. We propose to test this hypothesis with the following studies. 1.To calculate the interaction energies between various DAergic agonist and antagonist fragments and a carboxylate group (representing the receptor fragment) and to determine possible relationships between the calculated interaction energies and biological effects of DAergic drugs. 2.To synthesize and study permanently charged analogs of 3-(3-hydroxyphenyl)-N-n-propylpyridine (3-PPP). It has been postulated that the hydrogen on the amine group of 3-PPP is critical for determining activity at the dopamine receptor. 3.To synthesize and study hydrazinium (Aza) analogs of DAergic agonist and antagonist molecules that contain both a permanent positively charged group and a group that can act as a hydrogen bond donor. 4.To synthesize a set of formamidino, guanidino and thiourea analogs of DA, in order to investigate the overall importance of hydrogen bonding in the interaction of DAergic drugs with DAergic receptors.
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