Massively parallel screening of the receptorome

Area of Science:

• Pharmacology and Neuroscience
• Drug Discovery and Development
• Biochemistry

Background:

• The National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (PDSP) offers free screening of novel compounds to academic researchers.
• The PDSP utilizes a comprehensive panel of transmembrane receptors, channels, and transporters, covering a significant portion of the neuro-receptorome.

Purpose of the Study:

• To review the research applications of the PDSP resource, highlighting its utility in identifying drug side effects and mechanisms of action.
• To showcase recent findings demonstrating the program's impact on medication safety and understanding therapeutic targets.

Main Methods:

• Screening of novel chemical compounds against a large panel of neuroreceptors, channels, and transporters.
• Analysis of screening data to identify receptor interactions, off-target effects, and potential mechanisms of action.
• Case studies illustrating the application of PDSP findings in drug development and safety assessment.

Main Results:

• Identification of histamine H(1) receptor agonism as a cause of weight gain with antipsychotics.
• Association of 5-HT(2B) receptor agonism with cardiac valvulopathy, leading to medication withdrawal.
• Elucidation of the kappa opioid receptor as the target of salvinorin A and the dopaminergic action of WAY 100635.
• Discovery of M(1) muscarinic receptor activation by desmethylclozapine, potentially contributing to clozapine's efficacy.
• Identification of agonists for engineered designer receptors (DREADDs).

Conclusions:

• The PDSP is a valuable resource for identifying medication side effects and elucidating mechanisms of action for both existing and novel compounds.
• The program facilitates drug safety by uncovering adverse effects and aids in understanding therapeutic benefits by identifying molecular targets.
• The PDSP's broad screening capabilities support diverse research areas, including the study of engineered receptors.