D1-like receptors stimulate adenyl cyclase (AC) and phospholipase C through Gαs to increase cAMP (Figure 1). Recognized as a neurotransmitter in the 1950s,5 Cools and van Rossum rationalized that there must be multiple dopamine receptors (DRs) to facilitate the broad actions of 1 in the periphery and CNS.6 Employing biochemical methods, Spano7 and Kebabian8 identified two DRs, both G protein-coupled receptors (GPCRs) or Seven Transmembrane Receptors (7-TMRs), coined D1like and D2-like receptors. Dopamine (1), a catecholamine neurotransmitter, is a predominant neurotransmitter in the mammalian CNS and periphery with a myriad of physiological functions including movement, emotion, cognition, food intake, reinforcement/reward, cardiovascular function, hormone secretion and renal function to list but a few.1-4 As there are over 50 years of excellent reviews on differentĪspects of dopamine receptors,1-4 we will provide a brief overview to set the stage for the readers unfamiliar with the topic. This Perspective will review the historical data for D4, review the known D4 ligands, and then highlight new data supporting a role for D4 inhibition in addiction, PD and cancer.ĭopamine receptors. Not only D1-3,5, but also other biogenic amine targets, have emerged, and D4 is once again in the spotlight as a novel target for both addiction and Parkinson’s disease (PD), as well as other emerging diseases. Recently, D4 ligands with improved selectivity for D4 against Thus, D4 fell out of favor as a therapeutic target, and work in this area was silent for decades. Unfortunately, D4 antagonists that were developed for Keywords: G Protein-Coupled Receptor, Seven Transmembrane Receptor, dopamine, dopamine receptor subtype 4 (D4), schizophrenia, Parkinson’s disease (PD), L-745,870ĪBSTRACT: The dopamine D4 receptor garnered a great deal of interest in the early 1990s when studies showed the atypical antipsychotic clozapine possessed higher affinity for D4, relative to other dopamine receptor subtypes, and that this activity might underlie the unique clinical efficacy of clozapine. Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232ĭepartment of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN Hopkins5*ĭepartment of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232ĭepartment of Chemistry, Vanderbilt University, Nashville, TN 37232 The Return of D4 Dopamine Receptor Antagonists in Drug Discovery Craig W. However, no copyright claim is made to original U.S. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Journal of Medicinal Chemistry is published by the American Chemical Society. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. ![]() ![]() “Just Accepted” is an optional service offered to authors. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. ![]() “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. They are posted online prior to technical editing, formatting for publication and author proofing. Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |