GRANT=6673597;P20RR The long range objective of this research is to determine how clinically-proven antipsychotic drugs, and a new generation of dopamine D4 receptor selective drugs with potential anti-attention deficit hyperactivity disorder (ADHD) activity, selectively recognize their dopamine and/or serotonin receptor targets. A detailed understanding of the molecular interactions of antipsychotics and anti-ADHD drugs will have important clinical applications (i.e., bench-to-bedside), since an estimated 6% of the world's population is diagnosed with schizophrenia or ADHD. Many patients receive only partial benefit from current pharmacotherapies, and a variety of treatment-induced side-effects continue to be a source of non-compliance for those patients that do derive some benefit. In addition, antipsychotic drugs are being prescribed with increasing frequency to treat a range of neurological disorders other than schizophrenia. Consequently, the need to develop more effective and better-tolerated medications is continuing to increase. This growing need can be met by understanding the manner in which these drugs recognize their biogenic amine G protein-coupled receptor (GPCR) targets at the molecular level.
The specific aims of this proposal are: 1. To determine the amino acid side chain requirements in the second transmembrane spanning (TMS2) domain at positions 2.60 and 2.61 on the dopamine D4 receptor that are both necessary and sufficient for the binding and functional antagonism of structurally diverse D4-selective drugs, 2. To determine whether any generalizations concerning the molecular recognition of a broad range of antipsychotic drugs by dopamine D2 and D4 receptors can be made with respect to the length of the drugs' spacer arms. An assumption that a drug's spacer arm needs to tether an aromatic moiety in order to recognize TMS2 sites on dopamine receptors will also be explicitly tested, and 3. To determine whether amino acids in TMS2 of serotonin 5-HT2A and 5-HT2C receptor subtypes are critical for their high affinity interactions with antipsychotics and their >500-fold 5-HT2A/5-HT2C selectivity ratio for butyrophenones. Only positions 2.53, 2.60, 2.62, and 2.64 on serotonin receptors will be considered, because these are the only positions in TMS2 that are believed to be facing the binding pocket and that have different amino acids for the two subtypes.
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