Review on allosteric modulators of dopamine receptors so far

Abstract

AbstractBackgroundContemporary research is predominantly directed towards allosteric modulators, a class of compounds designed to interact with specific sites distinct from the orthosteric site on G protein‐coupled receptors. These allosteric modulators play a pivotal role in influencing diverse pharmacological effects, such as agonism/inverse agonism, efficacy modulation, and affinity modulation. One particularly intriguing aspect is the demonstrated capacity of allosteric modulation to enhance drug selectivity for therapeutic purposes, potentially leading to a reduction in serious side effects associated with traditional approaches. Allosteric ligands, a majority of which fall into the categories of negative allosteric modulators or positive allosteric modulators, exhibit the unique ability to either diminish or enhance the effects of endogenous ligands. Negative allosteric modulators weaken the response, while positive allosteric modulators intensify it. Additionally, silent allosteric modulators represent a distinct class that neither activates nor blocks the effects of endogenous ligands, adding complexity to the spectrum of allosteric modulation. In the broader context of central nervous system disorders, allosteric modulation takes center stage, particularly in the realm of dopamine receptors specifically, D1, D2, and D3 receptors. These receptors hold immense therapeutic potential for a range of conditions spanning neurodegenerative disorders to neurobehavioral and psychiatric disorders. The intricate modulation of dopamine receptors through allosteric mechanisms offers a nuanced and versatile approach to drug development. As research endeavors continue to unfold, the exploration of allosteric modulation stands as a promising frontier, holding the potential to reshape the landscape of drug discovery and therapeutic interventions in the field of neurology and psychiatry.