Dopamine and Serotonin Receptors: Selective or Multitarget Ligands for the Treatment of Central Nervous System Diseases

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 25 March 2025 | Viewed by 4314

Special Issue Editors


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Guest Editor
Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, 62032 Camerino, Italy
Interests: receptor chemistry; drug discovery; biologically active ligands; structure-activity relationship studies

E-Mail Website
Guest Editor
Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, 62032 Camerino, Italy
Interests: drug discovery; receptor ligands; structure-activity relationship studies; bioactive compounds

Special Issue Information

Dear Colleagues,

Dopamine and serotonin neurotransmitter pathways play important roles in regulating several physiological functions in the central nervous system and are altered in numerous complex diseases, including psychiatric and neurodegenerative disorders. An efficacious strategy in the treatment of such pathologies involves the discovery and development of ligands selectively targeting dopamine or serotonin receptor subtypes, with limited side effects (“magic bullets”).

However, the multitarget or “magic shotgun” approach, combining dopamine and serotonin receptor systems, might produce improved results in the treatment of polyfactorial pathologies. Indeed, with respect to combined therapies, multitarget drugs may offer clear advantages, including reduced risk of drug interactions, more predictive pharmacokinetics, and better patient compliance.

In this Special Issue, authors are invited to submit original articles dealing with the discovery and/or development of subtype selective or multitarget ligands targeting dopamine and/or serotonin receptors potentially useful for the treatment of central nervous system diseases. Review articles focused on the recent findings concerning this area of investigation will also be welcome.

Dr. Fabio Del Bello
Dr. Wilma Quaglia
Guest Editors

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Keywords

  • dopamine and serotonin neurotransmission
  • selective dopamine receptor ligands
  • selective serotonin receptor ligands
  • multitarget agents
  • central nervous system pathologies
  • psychiatric disorders
  • neurodegenerative diseases

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Published Papers (2 papers)

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Review

30 pages, 12638 KiB  
Review
Multitarget-Directed Ligands Hitting Serotonin Receptors: A Medicinal Chemistry Survey
by Imane Ghafir El Idrissi, Angela Santo, Enza Lacivita and Marcello Leopoldo
Pharmaceuticals 2024, 17(9), 1238; https://doi.org/10.3390/ph17091238 - 19 Sep 2024
Viewed by 1128
Abstract
Serotonin (5-hydroxytryptamine, 5-HT) is a ubiquitous neurotransmitter in the human body. In the central nervous system, 5-HT affects sleep, pain, mood, appetite, and attention, while in the peripheral nervous system, 5-HT modulates peristalsis, mucus production, and blood vessel dilation. Fourteen membrane receptors mediate [...] Read more.
Serotonin (5-hydroxytryptamine, 5-HT) is a ubiquitous neurotransmitter in the human body. In the central nervous system, 5-HT affects sleep, pain, mood, appetite, and attention, while in the peripheral nervous system, 5-HT modulates peristalsis, mucus production, and blood vessel dilation. Fourteen membrane receptors mediate 5-HT activity. In agreement with the crucial roles played by 5-HT, many drugs target 5-HT receptors (5-HTRs). Therefore, it is unsurprising that many efforts have been devoted to discovering multitarget-directed ligands (MTDLs) capable of engaging one or more 5-HTRs plus another target phenotypically linked to a particular disease. In this review, we will describe medicinal chemistry efforts in designing MTDLs encompassing activity for one or more 5-HTRs, starting with atypical antipsychotics and moving to dual 5-HT1AR/serotonin transporter ligands, 5-HT6R antagonists/acetyl cholinesterases inhibitors, and 5-HT4R agonists/acetyl cholinesterases inhibitors. We will also provide an outlook on the most recent efforts made in the field. Full article
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20 pages, 2597 KiB  
Review
Allosteric Modulators of Serotonin Receptors: A Medicinal Chemistry Survey
by Leonardo Brunetti, Fabio Francavilla, Marcello Leopoldo and Enza Lacivita
Pharmaceuticals 2024, 17(6), 695; https://doi.org/10.3390/ph17060695 - 28 May 2024
Viewed by 2679
Abstract
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter regulating numerous physiological functions, and its dysregulation is a crucial component of the pathological processes of schizophrenia, depression, migraines, and obesity. 5-HT interacts with 14 different receptors, of which 5-HT1A-1FRs, 5-HT2A-CRs, and 5-HT [...] Read more.
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter regulating numerous physiological functions, and its dysregulation is a crucial component of the pathological processes of schizophrenia, depression, migraines, and obesity. 5-HT interacts with 14 different receptors, of which 5-HT1A-1FRs, 5-HT2A-CRs, and 5-HT4-7Rs are G protein-coupled receptors (GPCRs), while 5-HT3R is a ligand-gated ion channel. Over the years, selective orthosteric ligands have been identified for almost all serotonin receptors, yielding several clinically relevant drugs. However, the high degree of homology between 5-HTRs and other GPCRs means that orthosteric ligands can have severe side effects. Thus, there has recently been increased interest in developing safer ligands of GPCRs, which bind to less conserved, more specific sites, distinct from that of the receptor’s natural ligand. The present review describes the identification of allosteric ligands of serotonin receptors, which are largely natural compounds (oleamide, cannabidiol, THC, and aporphine alkaloids), complemented by synthetic modulators developed in large part for the 5-HT2C receptor. The latter are positive allosteric modulators sought after for their potential as drugs preferable over the orthosteric agonists as antiobesity agents for their potentially safer profile. When available, details on the interactions between the ligand and allosteric binding site will be provided. An outlook on future research in the field will also be provided. Full article
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