Allosteric Modulators of Dopamine D2 Receptors for Fine-Tuning of Dopaminergic Neurotransmission in CNS Diseases: Overview, Pharmacology, Structural Aspects and Synthesis

Abstract

Allosteric modulation of G protein-coupled receptors (GPCRs) is nowadays a hot topic in medicinal chemistry. Allosteric modulators, i.e., compounds which bind in a receptor site topologically distinct from orthosteric sites, exhibit a number of advantages. They are more selective, safer and display a ceiling effect which prevents overdosing. Allosteric modulators of dopamine D2 receptor are potential drugs against a number of psychiatric and neurological diseases, such as schizophrenia and Parkinson’s disease. In this review, an insightful summary of current research on D2 receptor modulators is presented, ranging from their pharmacology and structural aspects of ligand-receptor interactions to their synthesis.

Understanding the Mechanisms of Action and Effects of Drugs of Abuse

“…In this regard, the primary reinforcing effects of abuse substances have been linked to the elevation of dopamine in the nucleus accumbens by either stimulating the dopamine neurons in the VTA or inhibiting the reuptake of the dopamine in the NAc [ 3 ]. Dopamine-receptors (DA-receptors) are widely distributed in the brain (mainly in the central nervous system and peripheral nervous system), play a key role in reward-related phenomena (in the ventral tegmental area), and are divided into two pharmacological families: D1-like receptors (D1R subtype—with effects on memory, attention, locomotion, impulse control, and regulation of renal function, and D5R subtype—with effects on decision making, cognition, attention, and renin secretion) and D2-like receptors (D2R subtype—with effects on locomotion, learning, attention, memory, sleep, D3R subtype—with effects on cognition, sleep, impulse control, attention, and DRD4 subtype—with effects on cognition, sleep, attention, and impulse control) [ 13 , 14 , 15 , 16 ]. The distribution and function of peripheral dopamine receptors have been described by Missale et al in 1988 and outlined effects such as inhibition of norepinephrine release (D2-like) and vasodilation (D1-like) on blood vessels, inhibition of aldosterone secretion (D2-like), stimulation of epinephrine/norepinephrine release (D1-like) and inhibition of epinephrine/norepinephrine release (D2-like) on the adrenal gland, increase of filtration rate (D1-like), stimulation of renin secretion (D1-like), inhibition of Na+ reabsorption (D1-like), inhibition of vasopressin action (d2-like), and inhibition of norepinephrine release (D2-like) on kidneys [ 14 ].…”

Dopamine D1–D5 Receptors in Brain Nuclei: Implications for Health and Disease

“…Another approach is to develop D2 receptor allosteric modulators, which bind to a distinct site from the orthosteric site and enhance or inhibit the binding and efficacy of the endogenous ligand or other drugs. For instance, PAOPA is a positive allosteric modulator of D2 receptors, which increases the affinity and potency of dopamine and D2 receptor agonists, and reverses the motor and cognitive impairments induced by D2 receptor antagonists [228,229]. In addition, a novel modulator of dopamine D2 receptors for the treatment of drug dependence exerts its therapeutic effect by suppressing the interaction between D2L receptors and FABP3 [127].…”

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…The choice of these receptors is due to rather extensive information about their allosteric sites and the diversity of their endogenous and synthetic allosteric regulators, including autoantibodies and synthetic pepducins. At the same time, for a number of other GPCRs, there is also a lot of data on allosteric regulation and their analysis is presented in a number of recent comprehensive reviews and analytical articles: for muscarinic acetylcholine receptors [ 171 , 172 , 173 , 174 ], for metabotropic glutamate receptors [ 171 , 175 , 176 ], for 5-hydroxytryptamine (serotonin) receptors [ 177 , 178 ], for dopamine receptors [ 177 , 179 ], for opioid receptors [ 178 , 180 , 181 ], for cannabinoid receptors [ 176 , 182 , 183 , 184 ], for adenosine receptors [ 185 ], for neuropeptide Y receptors [ 186 ], for melanocortin receptors [ 186 ], for angiotensin receptors [ 187 ], for glucagon-like peptide-1 receptors [ 176 , 188 ], and for free fatty acid receptors [ 58 ].…”