Recently an increasing number of potent neuronal nicotinic acetylcholine receptors (nAChRs) agonists have been used in experimental research and clinical trials, and have been found to display efficacy and/or a more selective affinity than nicotine for neuronal nAChR subtypes, some of which are considered potential candidates not only for the treatment of neurodegenerative diseases but also, for cognitive disorders associated with Schizophrenia. Focusing on the application of nicotinic agonists in psychotropic drug development for years, Creative Biolabs is professional and technical-mature in providing relative services.
Introduction to Nicotinic Receptors
Neuronal nicotinic acetylcholine receptors (nAChRs) belong to the superfamily of ligand-gated ion channels and are located in both the peripheral and central nervous systems. They are composed of five subunits and at present nine nicotinic receptor α subunits (α2-α10) and three β subunits (β2-β4) have been identified, each encoded by a different gene. In heterologous expression, nAChR can contain more than one of the α2, α3, α4 or α6 subunits and/or both β2 and β4 subunits as well. Accordingly, several different combinations of nAChR subunit mRNA and/or proteins have been identified in the central and peripheral nervous structures. The subunits α7, α8, α9, and α10 subunits can form homomeric receptors. These multiple combinations of nAChR subunits possess distinct pharmacological and physiological properties. Thus, nAChRs show a different affinity for ligands, the variability of permeability for cations, and the rate of desensitization.
Role of Nicotinic Receptor Subtypes in Psychiatric Disorders
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Preclinical Studies of α7 nAChR Agonists
Over the last decade, important progress has been made in the discovery of multiple full and partial α7 nAChR agonists. While early α7 nAChR ligands, such as DMXB-A, AR-R17779, and ABBF (EVP- 6124), had less favorable physicochemical properties and showed a lack of true subtype selectivity with off-target effects at hERG, 5-HT3, and/or α4β2 nAChR. Recently, disclosed α7 nAChR agonists possess improved selectivity and properties for oral dosing, including TC-5619. Despite the limitations of early α7 nAChR agonists, the characterization of novel ligands has provided exciting opportunities for critical proof-of-concept studies in animal models and, in some cases, clinical trials for schizophrenia and other neurological disorders.
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Preclinical Studies of α4β2 nAChR Agonists
Beyond the clear role of α7 nAChRs in the underlying auditory gating deficits observed in schizophrenic patients, there is accumulating evidence suggesting that altered α4β2 nAChR function may also have a role in the symptoms of this illness. To date, there have been several novel selective α4β2 nAChR agonists developed for the treatment of cognitive deficits associated with schizophrenia and other neurological disorders, including ABT-418, ABT-089, ABT-594, 5-iodo-A-85380, and TC-1734. However, unlike α7 nAChR agonists, α4β2 nAChR agonists produced robust effects in preclinical models of other attentional functions, such as in the five-choice serial reaction time task, and these effects were only blocked by α4β2 antagonists but not α7 antagonists.
Services at Creative Biolabs
Focusing on the novel psychotropic target discovery for years, Creative Biolabs has accumulated extensive professional experience from practice. With hundreds of customer-satisfied precedents, we are confident in the quality of our services that cover every aspect of psychotropic drug development, including target discovery, preclinical model development, and validation. We aim to promote industry development through our stand-alone services or integrated projects.
Why Us?
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Convenient: One-stop services
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Worry-free: Top-rated customer experience
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Efficient: Mature drug development system
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Reliable: Hundreds of successful precedents
With huge potential in psychotropic drug development, nicotinic agonists have aroused great interest. As an industry-leading CRO company, Creative Biolabs has focused on the application of nicotinic in target development for years. With extensive experience and mature technology, we are capable of providing relative development services to global researchers. If you have any questions, please feel free to contact us.
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