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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Lewandowicz, Anna M. Vepsäläinen, Jouko Laitinen, Jarmo T. |
| Description | Author Affiliation: Lewandowicz AM ( Department of Physiology, University of Kuopio, POB 1627, FIN-70211 Kuopio, Finland.) |
| Abstract | 1. Previous studies suggest that the thiadiazole compound SCH-202676 (N-(2,3-diphenyl-1,2,4-thiadiazol-5-(2H)-ylidene)methanamine) acts as an allosteric modulator of a variety of structurally distinct G protein-coupled receptors (GPCRs). It was postulated that SCH-202676 would directly bind a structural motif in the receptor molecule common to divergent members of the GPCR family. The molecular mechanisms of such a promiscuous action, however, remain obscure. 2. To clarify the mechanism of SCH-202676 action, we used the functional approach of [35S]GTPgammaS autoradiography with rat brain cryostat sections together with classical membrane [35S]GTPgammaS binding assays to evaluate how the thiadiazole affects G protein activity mediated by various receptors linked to the Gi-family of G proteins. 3. We found that in the absence of dithiotreitol (DTT), SCH-202676 (10(-7)-10(-5) M) elicits nonspecific effects in the [35S]GTPgammaS-based G protein activation assays, thereby severely compromising interpretations on the compounds ability to allosterically inhibit receptor-mediated G protein activity. Such a nonspecific behaviour was fully reversed upon addition of DTT (1 mM), revealing thiol-based mechanism of action. 4. In routine incubations containing DTT, SCH-202676 had no effect on receptor-driven G protein activity, as assessed for adenosine A1, alpha2-adrenergic, cannabinoid CB1, lysophosphatidic acid LPA1, muscarinic M2/M4, purinergic P2Y12 or sphingosine 1-phosphate receptors, suggesting that the thiadiazole does not act as an allosteric modulator of GPCR function. 5. 1H NMR analysis indicated that SCH-202676 underwent structural changes after incubation with the reducing agent DTT or with brain tissue. 6. We conclude that SCH-202676 modulates GPCRs via thiol modification rather than via true allosteric mechanisms. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 4 |
| Volume Number | 147 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2006-02-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Receptors, G-Protein-Coupled Metabolism Thiazoles Pharmacology Allosteric Regulation Animals Autoradiography Brain Chemistry Drug Effects Cell Membrane Guanosine 5'-O-(3-Thiotriphosphate) Nuclear Magnetic Resonance, Biomolecular Radioligand Assay Rats, Wistar Thiadiazoles |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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