GPCRs have proven highly successful as drug targets in the CNS. In 2002, nearly half of the 13 new CNS drugs approved by the U.S. Food & Drug Administration targeted these receptors.204 However, the development of drugs for CNS indications presents several unique and formidable challenges. The etiology, diagnosis, and treatment of mental illnesses include emotional and social aspects that may never be fully understood in terms of receptor pharmacology, making it particularly difficult to develop predictive preclinical disease models.

Drugs targeting GPCRs and other protein classes expressed in the CNS must be designed to cross the blood-brain barrier, which is a highly effective filter protecting the brain from exogenous compounds. In addition, system modulation or "fine tuning" of neurotransmitter circuits in the brain may be more desirable than complete blockade or sustained activation of receptor targets, perhaps through small molecule allosteric modulators of GPCRs.

Other important areas for GPCR-related research in the CNS include mapping of receptor expression at the single-cell and synaptic levels, analysis of cell-specific and synapse-specific receptor signaling pathways, and better understanding of the roles of receptor protein complexes. Receptor interaction sites for peptide ligands and endogenous amino acid ligands such as glutamate may not be suitable for pharmacological agents that can penetrate the CNS. Exploiting the potential of allosteric modulators, inverse agonists, and partial agonists may provide valuable tool compounds for research into the functions of GPCRs along with important new CNS disease therapies.

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