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Receptors have well-conserved regions that are recognized and activated by hormones and neurotransmitters. Most drugs bind to these sites and mimic or block the action of the native ligands. Using a high-throughput functional screen, we identified a potent and selective M(1) muscarinic receptor agonist from a novel structural class. Using a series of(More)
The primary purpose of the present series of experiments was to characterize the in vitro and in vivo pharmacology profile of 2-(4-methoxy-phenyl)-N-(4-methyl-benzyl)-N-(1-methyl-piperidin-4-yl)-acetamide hydrochloride (AC-90179), a selective serotonin (5-HT2A) receptor inverse agonist, in comparison with the antipsychotics haloperidol and clozapine. The(More)
Dopamine D(2) receptor antagonism contributes to the therapeutic action of antipsychotic drugs (APDs) but also produces undesirable side effects, including extrapyramidal motor deficits, cognitive dulling, and prolactinemia. The introduction of atypical APDs was a significant advancement in the treatment of schizophrenia. Whereas these agents are D(2)(More)
No safe, tolerated, and effective treatment for Parkinson's disease psychosis (PDP) is available; however, clozapine and quetiapine are often used off-label. An ideal PDP drug should have a therapeutic window that alleviates psychotic symptoms at doses that allow for maintained motor control and do not cause sedation. The present study determined the(More)
Most atypical antipsychotic drugs (APDs), e.g. risperidone (RIS), produce more extensive blockade of brain serotonin (5-HT)(2A) than dopamine (DA) D(2) receptors. This distinguishes them from typical APDs, e.g. haloperidol (HAL). Our objective was to test the hypothesis that augmentation of low doses of RIS or HAL (2mg/day) with pimavanserin (PIM), a(More)
Explicit molecular binding pockets were constructed and optimized around sets of superimposed ligands using the minireceptor concept. The resulting binding sites incorporate the properties of the different ligands and were shown to be suitable for the design of molecules presenting novel interaction patterns. Two applications of minireceptor construction(More)
Parkinson’s disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson’s patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in(More)
1. Factors influencing agonist affinity and relative efficacy have been studied for the 5-HT(1A) serotonin receptor using membranes of CHO cells expressing the human form of the receptor and a series of R-and S-2-(dipropylamino)tetralins (nonhydroxylated and monohydroxylated (5-OH, 6-OH, 7-OH, 8-OH) species). 2. Ligand binding studies were used to determine(More)
(-)-OSU6162 has promise for treating Parkinson's disease, Huntington's disease and schizophrenia. Behavioral tests evaluating the locomotor effects of (-) and (+)-OSU6162 on 'low activity' animals (reserpinized mice and habituated rats) and 'high activity' animals (drug naive mice and non-habituated rats) revealed that both enantiomers of OSU6162 had dual(More)
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