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Various Receptors (various + receptor)
Selected AbstractsPeptide-based radiopharmaceuticals: Future tools for diagnostic imaging of cancers and other diseasesMEDICINAL RESEARCH REVIEWS, Issue 3 2004S.M. Okarvi Abstract An Erratum has been published for this article in Medicinal Research Reviews 2004;24:685,686. Small synthetic receptor-binding peptides are the agents of choice for diagnostic imaging and radiotherapy of cancers due to their favorable pharmacokinetics. Molecular modification techniques permit the synthesis of a variety of bioactive peptides with chelating groups, without compromising biological properties. Various techniques have been developed that allow efficient and site-specific labeling of peptides with clinically useful radionuclides such as 99mTc, 123I, 111In, and 18F. Among them, 99mTc is the radionuclide of choice because of its excellent chemical and imaging characteristics. Recently, many 99mTc-labeled peptides have proven to be useful imaging agents. Beside 99mTc-labeled peptides, several peptides radiolabeled with 111In and 123I have been prepared and characterized. In addition, 18F-labeled peptides hold clinical potential due to their ability to quantitatively detect and characterize a variety of human diseases using positron-emission tomography. The availability of this wide range of peptides labeled with different radionuclides offers multiple diagnostic and therapeutic applications. Various receptors are over-expressed in particular tumor types and peptides binding to these receptors can be used to visualize tumor lesions scintigraphically. Thus, radiolabeled peptides have potential use as carriers for the delivery of radionuclides to tumors, infarcts, and infected tissues for diagnostic imaging and radiotherapy. Many radiolabeled peptides are currently under investigation to determine their potential as imaging agents. These peptides are designed mainly for thrombus, tumor, and infection/inflammation imaging. This article presents recent developments in small synthetic peptides for imaging of thrombosis, tumors, and infection/inflammation. © 2004 Wiley Periodicals, Inc. Med Res Rev, 24, No. 3, 357,397, 2004 [source] MDMA, methamphetamine and their combination: possible lessons for party drug users from recent preclinical researchDRUG AND ALCOHOL REVIEW, Issue 1 2007KELLY J. CLEMENS Abstract The substituted amphetamines 3,4-methylenedioxymethamphetamine (MDMA, ,Ecstasy') and methamphetamine (METH, ,ice', ,speed') are increasingly popular drugs amongst party-drug users. Studies with humans have investigated the acute and possible long-term adverse effects of these drugs, yet outcomes of such studies are often ambiguous due to a variety of confounding factors. Studies employing animal models have value in determining the acute and long-term effects of MDMA and METH on brain and behaviour. Self-administration studies show that intravenous METH is a particularly potent reinforcer in rats and other species. In contrast, MDMA appears to have powerful effects in enhancing social behaviour in laboratory animals. Brief exposure to MDMA or METH may produce long-term reductions in dopamine, serotonin and noradrenaline in the brain and alterations in the density of various receptor and transporter proteins. However it is still unclear, particularly in the case of MDMA, whether this reflects a ,neurotoxic' effect of the drug. Lasting alterations in social behaviour, anxiety, depressive symptoms and memory have been demonstrated in laboratory rats given MDMA or METH and this matches long-term changes reported in some human studies. Recent laboratory studies suggest that MDMA/METH combinations may produce greater adverse neurochemical and behavioural effects than either drug alone. This is of some concern given recent evidence that party drug users may be frequently exposed to this combination of drugs. [source] The ,allosteric modulator' SCH-202676 disrupts G protein-coupled receptor function via sulphydryl-sensitive mechanismsBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2006Anna M Lewandowicz 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. To clarify the mechanism of SCH-202676 action, we used the functional approach of [35S]GTP,S autoradiography with rat brain cryostat sections together with classical membrane [35S]GTP,S binding assays to evaluate how the thiadiazole affects G protein activity mediated by various receptors linked to the Gi -family of G proteins. We found that in the absence of dithiotreitol (DTT), SCH-202676 (10,7,10,5 M) elicits nonspecific effects in the [35S]GTP,S-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. In routine incubations containing DTT, SCH-202676 had no effect on receptor-driven G protein activity, as assessed for adenosine A1, ,2 -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. 1H NMR analysis indicated that SCH-202676 underwent structural changes after incubation with the reducing agent DTT or with brain tissue. We conclude that SCH-202676 modulates GPCRs via thiol modification rather than via true allosteric mechanisms. British Journal of Pharmacology (2006) 147, 422,429. doi:10.1038/sj.bjp.0706624 [source] Mapping the Specific Cytoprotective Interaction of Humanin with the Pro-apoptotic Protein BidCHEMICAL BIOLOGY & DRUG DESIGN, Issue 5 2007Jungyuen Choi Humanin is a short endogenous peptide, which can provide protection from cell death through its association with various receptors, including the pro-apoptotic Bcl-2 family proteins Bid, Bim, and Bax. By using NMR chemical shift mapping experiments, we demonstrate that the interaction between Humanin-derived peptides and Bid is specific, and we localize the binding site to a region on the surface of Bid, which includes residues from the conserved helical BH3 domain of the protein. The BH3 domain mediates the association of Bid with other Bcl-2 family members and is essential for the protein's cytotoxic activity. The data suggest that Humanin exerts its cytoprotective activity by engaging the Bid BH3 domain; this would hinder the association of Bid with other Bcl-2 family proteins, thereby mitigating its toxicity. The identification of a Humanin-specific binding site on the surface of Bid reinforces its importance as a direct modulator of programmed cell death, and suggests a strategy for the design of cytoprotective peptide inhibitors of Bid. [source] The Enantiomer of Octreotate Binds to All Five Somatostatin Receptors with Almost Equal Micromolar Affinity , A Comparison with SANDOSTATIN®CHEMISTRY & BIODIVERSITY, Issue 7 2008James Gardiner Abstract Octreotate (1b) is the octreotide (SANDOSTATIN®; 1a) analogue, carrying a C-terminal CO2H (Thr) instead of the CH2OH (threoninol) group. In pursuit of our interest in unnatural peptides, we have now synthesized (by the solid-phase Fmoc method) the enantiomeric form 2 of octreotate and determined its affinity for the five human somatostatin (SRIF) receptors (hsst1,5). The binding was found to be 9.1, 4.1, 1.0, 1.4, and 4.2,,M, respectively. This almost equal one-digit micromolar affinity of ent -octreotate (2) to all five receptors contrasts with the behavior of most other somatostatin mimics including SANDOSTATIN® (octreotide; 1a) and [Tyr3]-octreotate (1c), which have affinities for the various receptors differing up to and above 104 -fold. Thus, the structure of the new compound does not prevent binding, albeit more weakly than its pseudo -enantiomer octreotide, and there is hardly any selectivity of the peptide,protein interaction (PPI) for any one of the five SRIF G-protein coupled receptors (GPCRs). Since the detailed structure(s) of these membrane-embedded receptors is unknown (no X-ray structure!), the result described here may be useful for modeling structures by comparing the affinities of the numerous known somatostatin mimics. [source] | ||||||||||