Abstract
Schizophrenia was first described by Emil Krapelin in the 19th century as one of the major mental illnesses causing disability worldwide. Since the introduction of chlorpromazine in 1952, strategies aimed at modifying the activity of dopamine receptors have played a major role for the treatment of schizophrenia. The introduction of atypical antipsychotics with clozapine broadened the range of potential targets for the treatment of this psychiatric disease, as they also modify the activity of the serotoninergic receptors. Interestingly, all marketed drugs for schizophrenia bind to the orthosteric binding pocket of the receptor as competitive antagonists or partial agonists. In recent years, a strong effort to develop allosteric modulators as potential therapeutic agents for schizophrenia was made, mainly for the several advantages in their use. In particular, the allosteric binding sites are topographically distinct from the orthosteric pockets, and thus drugs targeting these sites have a higher degree of receptor subunit specificity. Moreover, “pure” allosteric modulators maintain the temporal and spatial fidelity of native orthosteric ligand. Furthermore, allosteric modulators have a “ceiling effect”, and their modulatory effect is saturated above certain concentrations. In this review, we summarize the progresses made in the identification of allosteric drugs for dopamine and serotonin receptors, which could lead to a new generation of atypical antipsychotics with a better profile, especially in terms of reduced side effects.
Highlights
Dopamine is a catecholamine neurotransmitter that plays an important role in the central nervous system and exerts its function by binding to dopamine receptors [1]
The existence of dopamine receptors was first revealed in 1972 with the demonstration that dopamine was the major activator of a retinal adenylyl cyclase activity [7], and later on it became apparent that dopamine receptors exist in multiple forms [8]
We summarize the recent discovery of new allosteric compounds for dopamine and serotonin receptors that can influence the underlying molecular mechanisms of schizophrenia
Summary
Dopamine is a catecholamine neurotransmitter that plays an important role in the central nervous system and exerts its function by binding to dopamine receptors [1]. Works like NAM, and functions as an inverse agonist without the orthosteric ligand it modulates Another level of complexity is added by the influence of allosteric ligands on GPCR homoand heterodimerization. The main advantage is that allosteric modulators with a defined fold shift of agonist potency may reduce toxicity or avoid overdosing of the patient [39] This is relevant in schizophrenia, where antipsychotic medication titration to a therapeutic dose is often difficult without unacceptable adverse effects [40]. Most second-generation antipsychotic drugs are serotonin receptor antagonists/partial agonists and bind with high affinity to 5-HT1A, 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors [59].
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