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Peptide Antagonist (peptide + antagonist)
Selected AbstractsCharacterization of nociceptin binding sites by novel peptide analogs and radioprobesJOURNAL OF NEUROCHEMISTRY, Issue 2003S. Benyhe A number of new synthetic nociceptin ligands were studied in receptor binding and functional tests in rat brain membranes and in cloned systems. Ligand binding experiments were performed with three different radioprobes developed in our lab. The nociceptin derivatives exhibited high affinity in competition experiments. Receptor-mediated G-protein activation was determined in [35S]GTPgS binding assays. Among the new structures examined, Ac-RYYRIK-ol was found to be only a weak stimulator by itself, whereas this compound inhibited receptor-mediated G-protein activation. These data suggest that Ac-RYYRIK-ol is a high affinity peptide antagonist for the nociceptin receptor. Acknowledgements:, Supported by the Hungarian Scientific Research Fund OTKA T-035211, T-033078, T-030841, and the Ministry of Education, NKFP 1/027 Hungary. [source] Calmodulin activity and cAMP signalling modulate growth and apical secretion in pollen tubesTHE PLANT JOURNAL, Issue 6 2004Cláudia Rato Summary Our present understanding implicates both calmodulin (CaM) and 3,,5,-cyclicAMP (cAMP) in the regulation of pollen tube growth. However, downstream molecules of these signalling pathways and the cellular processes they modulate remain largely unknown. In order to elucidate the role of CaM, we mapped its activity in growing pollen tubes. 2-chloro-(,-amino-Lys75)-[6-4-(N,N, -diethylaminophenyl)-1,3,5-triazin-4-yl]-calmodulin (TA-CaM) and fluorescein-calmodulin (FL-CaM), fluorescent analogues of CaM, were loaded into pollen tubes and CaM activity was mapped by fluorescence ratio imaging. It was found that CaM activity exhibits a tip-focused gradient, similar to the distribution of cytosolic-free calcium ([Ca2+]c). In long pollen tubes, apical CaM activity was also found to oscillate with a period similar to [Ca2+]c (40,80 sec). This oscillatory behaviour was not observed in small pollen tubes or in tubes that had stopped growing. Changes in CaM activity within the dome of the pollen tube apex resulting from the photolysis of caged photolysis of RS-20 (a peptide antagonist of CaM) induced re-orientation of the growth axis, suggesting that CaM is also involved in the guidance mechanism. CaM activity was strongly modulated by intracellular changes in cAMP (induced by activators and antagonists of adenylyl cyclase). These results indicate that the action of this protein is dependent not solely on [Ca2+]c but also on a cross-talk with other signalling pathways. A putative target of this cross-talk is the secretory machinery as observed in pollen tubes loaded with the FM (N -(3-triethylammoniumpropyl)-4-(4-dibutylamino)styryl)pyridinium dibromide 1-43 dye and exposed to different antagonists and activators of these molecules. Our data thus suggest that pollen tube growth and orientation depend on an intricate cross-talk between multiple signalling pathways in which CaM is a key element. [source] Medullary pain facilitating neurons mediate allodynia in headache-related pain,ANNALS OF NEUROLOGY, Issue 2 2009Rebecca M. Edelmayer BS Objective To develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches. To explore neural mechanisms underlying cephalic and extracephalic allodynia. Methods Inflammatory mediators (IM) were applied to the dura of unanesthetized rats via previously implanted cannulas, and sensory thresholds of the face and hind-paws were characterized. Results IM elicited robust facial and hind-paw allodynia, which peaked within 3 hours. These effects were reminiscent of cutaneous allodynia seen in patients with migraine or other primary headache conditions, and were reversed by agents used clinically in the treatment of migraine, including sumatriptan, naproxen, and a calcitonin gene,related peptide antagonist. Consistent with clinical observations, the allodynia was unaffected by a neurokinin-1 antagonist. Having established facial and hind-paw allodynia as a useful animal surrogate of headache-associated allodynia, we next showed that blocking pain-facilitating processes in the rostral ventromedial medulla (RVM) interfered with its expression. Bupivacaine, destruction of putative pain-facilitating neurons, or block of cholecystokinin receptors prevented or significantly attenuated IM-induced allodynia. Electrophysiological studies confirmed activation of pain-facilitating RVM "on" cells and transient suppression of RVM "off" cells after IM. Interpretation Facial and hind-paw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for development of novel therapeutic strategies for headache pain. The data also demonstrate the requirement for activation of descending facilitation from the RVM for the expression of cranial and extracranial cutaneous allodynia, and are consistent with a brainstem generator of allodynia associated with headache disorders. Ann Neurol 2009;65:184,193 [source] Growth hormone secretagogue receptor antagonists as potential therapeutic agents for obesityDRUG DEVELOPMENT RESEARCH, Issue 2 2005Hongyu Zhao Abstract Safe and efficacious medicines for obesity treatment are greatly needed. As an endogenous ligand of growth hormone secretagogue receptor 1a (GHS-R 1a), ghrelin is the only known circulating orexigen. Administration of ghrelin causes food intake and body weight increase in both rodents and humans, whereas inhibiting its actions by antibodies, peptide antagonists, and anti-sense oligonucleotides leads to decreased food intake and weight loss. Recent progress in developing nonpeptidyl small molecule GHS-R antagonists is reviewed in this article. Drug Dev. Res. 65:50,54, 2005. © 2005 Wiley-Liss, Inc. [source] | |||||||||||||