Molecular pharmacology of metabotropic receptors targeted by neuropsychiatric drugs

Abstract

Metabotropic receptors are responsible for so-called slow synaptic transmission and mediate the effects of 100's of peptide and non-peptide neurotransmitters and neuromodulators. Over the past decade or so a revolution in membrane protein structural determination has clarified the molecular determinants responsible for the actions of these receptors. Here I focus on the G protein-coupled receptors (GPCRs) which are targets for neuropsychiatric drugs and show how insights into the structure and function of these important synaptic proteins are accelerating our understanding of their actions. Importantly, illuminating GPCR structure and function should enhance the structureguided discovery of novel chemical tools to manipulate and understand these synaptic proteins. MAIN Neurotransmitter receptors are essential for mediating the effects of neurotransmitters in the brain and peripheral nervous system. There are generally considered to be two types of neurotransmitter receptors: ionotropic and metabotropic. While ionotropic receptors are typically ligand-gated ion channels, through which ions pass in response to a neurotransmitter, metabotropic receptors require G proteins and second messengers to indirectly modulate ionic activity in neurons. G protein-coupled receptors (GPCRs) represent the largest family of metabotropic receptors, although receptor-tyrosine kinases 1 and guanylate cyclase receptors 2,3 can also be considered to be metabotropic receptors 4. GPCRs also constitute the largest family of druggable targets 56 in the human genome, and 34% of FDA-approved medications have GPCRs as their main therapeutic target 78especially those used for neuropsychiatric disorders 6,9,10 (Table 1).

G-Protein coupled receptors: structure and function in drug discovery

“…), which is a GABA B agonist used in the treatment of muscle spasms. 41,42,[44][45][46] The family C GPCRs differ from others by possessing a large extracellular domain, distal to the TMD receptors, and containing the orthosteric sites; they also form constitutive dimers with unique activation systems in comparison with other GPCR families. 41 Similarly, to their related families, family C GPCRs exhibit a typical motif of seven TMD helices however differ structurally from other GPCR families in their possession of an unusually large extracellular domain, an intracellular carboxylterminal (C-terminal) domain and a heptahelical TMD (Fig.…”

Discovery of Novel CCR5 Ligands as Anticolorectal Cancer Agents by Sequential Virtual Screening

“…This is remarkable considering that prospective VS campaigns often result in antagonists even when an agonist-bound VS model is used. 81 , 82 The distinct pharmacological profiles of MVC, compound 1 , and compound 3 need to be further assessed in functional assays.…”

Glutamate Receptors in Schizophrenia: A Review

“…After Cellular analysis it was revealed that this increase was due to enhanced expression of mGluR5 mRNA in pyramidal cells in lamina III of this area of prefrontal cortex. 24…”