Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics
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 s...
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MDPI AG
2020-11-01
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| author | Irene Fasciani Francesco Petragnano Gabriella Aloisi Francesco Marampon Marco Carli Marco Scarselli Roberto Maggio Mario Rossi |
| author_facet | Irene Fasciani Francesco Petragnano Gabriella Aloisi Francesco Marampon Marco Carli Marco Scarselli Roberto Maggio Mario Rossi |
| author_sort | Irene Fasciani |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T14:51:31Z |
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| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T14:51:31Z |
| publishDate | 2020-11-01 |
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| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-19ecbf2a566741ab86ff7dfba556f7992023-11-20T20:56:42ZengMDPI AGPharmaceuticals1424-82472020-11-01131138810.3390/ph13110388Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical AntipsychoticsIrene Fasciani0Francesco Petragnano1Gabriella Aloisi2Francesco Marampon3Marco Carli4Marco Scarselli5Roberto Maggio6Mario Rossi7Department of Biotechnological and Applied Clinical Sciences, University of l’Aquila, 67100 L’Aquila, ItalyDepartment of Biotechnological and Applied Clinical Sciences, University of l’Aquila, 67100 L’Aquila, ItalyDepartment of Biotechnological and Applied Clinical Sciences, University of l’Aquila, 67100 L’Aquila, ItalyDepartment of Radiotherapy, “Sapienza” University of Rome, Policlinico Umberto I, 00161 Rome, ItalyDepartment of Translational Research and New Technology in Medicine and Surgery, University of Pisa, 56126 Pisa, ItalyDepartment of Translational Research and New Technology in Medicine and Surgery, University of Pisa, 56126 Pisa, ItalyDepartment of Biotechnological and Applied Clinical Sciences, University of l’Aquila, 67100 L’Aquila, ItalyInstitute of Molecular Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, UKSchizophrenia 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.https://www.mdpi.com/1424-8247/13/11/388dopamine receptorserotonin (5-HT) receptorpositive allosteric modulatornegative allosteric modulatorendogenous allosteric modulatorallosteric binding site |
| spellingShingle | Irene Fasciani Francesco Petragnano Gabriella Aloisi Francesco Marampon Marco Carli Marco Scarselli Roberto Maggio Mario Rossi Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics Pharmaceuticals dopamine receptor serotonin (5-HT) receptor positive allosteric modulator negative allosteric modulator endogenous allosteric modulator allosteric binding site |
| title | Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics |
| title_full | Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics |
| title_fullStr | Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics |
| title_full_unstemmed | Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics |
| title_short | Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics |
| title_sort | allosteric modulators of g protein coupled dopamine and serotonin receptors a new class of atypical antipsychotics |
| topic | dopamine receptor serotonin (5-HT) receptor positive allosteric modulator negative allosteric modulator endogenous allosteric modulator allosteric binding site |
| url | https://www.mdpi.com/1424-8247/13/11/388 |
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