Dataset Information

Molecular and behavioral pharmacology of two novel orally-active 5HT2 modulators: potential utility as antipsychotic medications.

ABSTRACT:

Background

Desired serotonin 5HT2 receptor pharmacology for treatment of psychoses is 5HT2A antagonism and/or 5HT2C agonism. No selective 5HT2A antagonist has been approved for psychosis and the only approved 5HT2C agonist (for obesity) also activates 5HT2A and 5HT2B receptors, which can lead to clinical complications. Studies herein tested the hypothesis that a dual-function 5HT2A antagonist/5HT2C agonist that does not activate 5HT2B receptors would be suitable for development as an antipsychotic drug, without liability for weight gain.

Methods

The novel compounds (+)- and (-)-trans-4-(4'-chlorophenyl)-N,N-dimethyl-2-aminotetralin (p-Cl-PAT) were synthesized, characterized in vitro for affinity and functional activity at human 5HT2 receptors, and administered by intraperitoneal (i.p.) and oral (gavage) routes to mice in behavioral paradigms that assessed antipsychotic efficacy and effects on feeding behavior.

Results

(+)- and (-)-p-Cl-PAT activated 5HT2C receptors, with (+)-p-Cl-PAT being 12-times more potent, consistent with its higher affinity across 5HT2 receptors. Neither p-Cl-PAT enantiomer activated 5HT2A or 5HT2B receptors at concentrations up to 300-times greater than their respective affinity (Ki), and (+)-p-Cl-PAT was shown to be a 5HT2A competitive antagonist. When administered i.p. or orally, (+)- and (-)-p-Cl-PAT attenuated the head-twitch response (HTR) in mice elicited by the 5HT2 agonist (-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and reduced intake of a highly palatable food in non-food-deprived mice, with (+)-p-Cl-PAT being more potent across behavioral assays.

Conclusions

The novel in vitro pharmacology of (+)-p-Cl-PAT (5HT2A antagonism/5HT2C agonism without activation of 5HT2B) translated in vivo to an orally-active drug candidate with preclinical efficacy to treat psychoses without liability for weight gain.

SUBMITTER: Morgan D

PROVIDER: S-EPMC3696402 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Publications

Molecular and behavioral pharmacology of two novel orally-active 5HT2 modulators: potential utility as antipsychotic medications.

Morgan Drake D Kondabolu Krishnakanth K Kuipers Allison A Sakhuja Rajeev R Robertson Kimberly L KL Rowland Neil E NE Booth Raymond G RG

Neuropharmacology 20130509

<h4>Background</h4>Desired serotonin 5HT2 receptor pharmacology for treatment of psychoses is 5HT2A antagonism and/or 5HT2C agonism. No selective 5HT2A antagonist has been approved for psychosis and the only approved 5HT2C agonist (for obesity) also activates 5HT2A and 5HT2B receptors, which can lead to clinical complications. Studies herein tested the hypothesis that a dual-function 5HT2A antagonist/5HT2C agonist that does not activate 5HT2B receptors would be suitable for development as an ant ...[more]

PMID: 23665356

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Project description:OBJECTIVES:To compare the risk of major medical events in nursing home residents newly initiated on conventional or atypical antipsychotic medications (APMs). DESIGN:Cohort study, using linked Medicaid, Medicare, Minimum Data Set, and Online Survey Certification and Reporting data. Propensity score-adjusted proportional hazards models were used to compare risks for medical events at a class and individual drug level. SETTING:Nursing homes in 45 U.S. states. PARTICIPANTS:Eighty-three thousand nine hundred fifty-nine Medicaid-eligible residents aged 65 and older who initiated APM treatment after nursing home admission in 2001 to 2005. MEASUREMENTS:Hospitalization for myocardial infarction, cerebrovascular events, serious bacterial infections, and hip fracture within 180 days of treatment initiation. RESULTS:Risks of bacterial infections (hazard ratio (HR) = 1.25, 95% confidence interval (CI) = 1.05-1.49) and possibly myocardial infarction (HR = 1.23, 95% CI = 0.81-1.86) and hip fracture (HR = 1.29, 95% CI = 0.95-1.76) were higher, and risks of cerebrovascular events (HR = 0.82, 95% CI = 0.65-1.02) were lower in participants initiating conventional APMs than in those initiating atypical APMs. Little variation existed between individual atypical APMs, except for a somewhat lower risk of cerebrovascular events with olanzapine (HR = 0.91, 95% CI = 0.81-1.02) and quetiapine (HR = 0.89, 95% CI = 0.79-1.02) and a lower risk of bacterial infections (HR = 0.83, 95% CI = 0.73-0.94) and possibly a higher risk of hip fracture (HR = 1.17, 95% CI = 0.96-1.43) with quetiapine than with risperidone. Dose-response relationships were observed for all events (HR = 1.12, 95% CI = 1.05-1.19 for high vs low dose for all events combined). CONCLUSION:These associations underscore the importance of carefully selecting the specific APM and dose and monitoring their safety, especially in nursing home residents who have an array of medical illnesses and are undergoing complex medication regimens.

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Dataset Information

Molecular and behavioral pharmacology of two novel orally-active 5HT2 modulators: potential utility as antipsychotic medications.

Background

Methods

Results

Conclusions

Publications

Molecular and behavioral pharmacology of two novel orally-active 5HT2 modulators: potential utility as antipsychotic medications.

Similar Datasets

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