Peptide-antagonists

The synthesis of peptide antagonists has greatiy aided in the development of knowledge of other neuropeptide systems as well. 

The CCK system shares one property with the opioid system, ie, the existence of selective nonpeptide antagonists. These include aspedicine, a natural benzodiazepine (136), and Devazepide (L-364,718 MK-329) (137). Selective, potent peptide antagonists for CCK, eg, Cl-988 and PD 134308, have been developed that maybe useful as anxiolytics and as dmgs which increase the analgesic effect of morphine but at the same time prevent morphine tolerance (138) (see Hypnotics, sedatives, anticonvulsants, and anxiolytics). 

Receptor N-terminal tethered tigand Proteinase agonists Peptide agonists3 Proteinase/Peptide/Non peptide antagonists... 

While the agonist binding domain is thought to be within the transmembrane domains for the monoamine and nucleotide receptors, neuropeptides are thought to bind close to the membrane surface on the extracellular domains of the receptor. It is still not clear whether non-peptide antagonists bind at the same or a different site on the receptor. 

Again, the existence of non-peptide antagonists at these receptors will soon lead to a better understanding of the central roles of this peptide. 

Nearly all the clinical data comes from the use of atosiban (see Peptide Antagonists), a peptide oxytocin antagonist that is licensed in Europe for acute (48 h) treatment of preterm labour. Early clinical studies demonstrated the ability of atosiban to inhibit uterine contractions associated with labour [14]. Following these successful phase II trials, full phase III trials were... 

The search for an effective non-peptide oxytocin antagonist has become a major goal of a number of pharmaceutical companies because of the poor pharmacokinetic properties and especially the lack of oral bioavailability associated with peptidic antagonists. Early research in this field was dominated by Merck, but in recent years significant research efforts at GlaxoSmithKline and Serono have been published. A number of other companies, notably Sanofi-Aventis, Yamanouchi and Wyeth, have had a major presence in vasopressin receptor research and oxytocin is frequently included in patent claims for the molecules. Occasionally, oxytocin-selective compounds have been reported, usually derived by adaptation of the vasopressin antagonist template. 

Horuk R, Shurey S, Ng HP, et al. CCRl-specific non-peptide antagonist efficacy in a rabbit allograft rejection model. Immunol Lett 2001 76 193-201. 

Different approaches have been used to probe the role of chemokines and their receptors in experimental models of arthritis for instance, peptide antagonists or immunization of the host to promote the generation of endogenous neutralizing Abs via the use of chemokine plasmid DNA vaccination (Table 4 and Ref. 50), injection of neutralizing antibodies (Table 5), or mice that lack specific chemokine or chemokine receptors (Table 6). 

Lee PHK, Nguyen TM-D, Chung NN, Schiller PW, Chang KJ. Tyrosine-iodination converts the delta opioid peptide antagonist TIPP to an agonist. Eur J Pharmacol 1995 280 211-214. 

Like angiotensin 11, non-peptide B2 receptor antagonists and agonists of bradykinin were obtained by random screening approaches. Chemical modifications on random screening leads like 101 led to non-peptide antagonists... 

Non-peptide antagonists of endothelin were discovered by random screening approaches. A comparison of compounds 119 and 120 demonstrates that it is possible to obtain selective and non-selective compounds in the same series by chemical modifications. Carboxyindoline derivative 119 was about 100-fold more selective ETa receptor antagonist and compound 120 was a non-selective antagonist. Another series of... 

Recent examples of successful peptide-ligand based discoveries of drug-like peptidomimetics include the discovery of SST antagonists, or the discovery of non-peptidic antagonists of the recently deorphanized urotensin II receptor at Sanofi-Aventis. ° As illustrated in Fig. 3, Flohr etal. used 3D models of the NMR solution structure of cyclic peptide derivatives of Urotensin II as a template for virtual 3D pharmacophore searches which resulted into non-peptidic candidates for lead optimization. 

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