Conformationally restricted analogs of somatostatin with high mu-opiate receptor specificity.

Abstract

The cyclic tetradecapeptide somatostatin is known to interact with a variety of receptor systems over a wide concentration range (1). High-affinity (low dissociation constant) binding with a receptor system is generally thought to have physiological significance, but when the affinity is weak (micromolar), the physiological significance is not clear. The weak affinity that somatostatin displays for the opiate receptor is one such example. It We have prepared a number of conformationally restricted analogs of somatostatin in order to probe the structural and conformational features important for somatostatin's activity at opiate receptors. These studies have resulted in the de- MATERIALS AND METHODS Somatostatin was purchased from Vega Biotechnologies.The analog CGP 23,996 (des-Ala', Gly2-[desamino-Cys3, Tyr"]-3,14-dicarbasomatostatin) was a generous gift from CIBA-Geigy. Amino acid analyses were performed on a Beckman 120C amino acid analyzer. All optically active amino acids are of the L variety unless otherwise noted. Cysteine was determined as cysteic acid (5). Fast-atom-bombardment mass spectra (FABMS) were obtained on a Varian 311A spectrometer equipped with an Ion Tech Ltd source with xenon as the bombarding gas.Analogs were synthesized by standard solid-phase synthetic techniques (6,7). N`,-t-Butyloxycarbonyl (Boc)-protected amino acids were used throughout the syntheses and were prepared in the usual manner (8,9). For the preparation of peptides with a COOH-terminal carboxylic acid group, N`a-t-Boc-O-Bzl-L-threonine (Bzl = benzyl) was attached to chloromethylated copoly(styrene-1% divinylbenzene) beads (Lab Systems, 0.71 milliequivalent of Cl per g of resin) by the method of Gisin (10). Carboxamide peptides were prepared with a p-methylbenzhydrylamine resin (threonine substitution, 0.35 mmol/g of resin) as described (7). Preformed symmetrical anhydrides were used in the coupling reactions

Excessive grooming induced by somatostatin or its analog SMS 201-995

“…Since peptide-induced scratching is mainly due to activation of opiate receptor systems (Van Wimersma Greidanus et al, 1985b;Spruijt et al, 1986a) this observation indicates that opiate receptors are involved in the behavioral response to SMS 201-995 and somatostatin. This is consistent with the suggestion by Terenius (1976) that somatostatin acts as partial agonistantagonist on opiate receptors in the CNS, and with other reports on opiate-like actions of somatostatin and some of its analogs (Rezek et al, 1978;Pelton et al, 1985). Interestingly, the contribution of the scratching element to SMS 201-995-induced grooming was most pronounced after doses ranging from 50 to 100 ng.…”

Synthetic NGF peptide derivatives prevent neuronal death via a p75 receptor-dependent mechanism

“…One cysteine and one penicillamine (b,b-dimethylcysteine) residue were added to each end of the linear sequence to provide sulfhydryl groups for oxidative peptide cyclization. Penicillamine has been found to facilitate cyclization and provide greater conformational constraint relative to cysteine-cysteine cyclization (Pelton et al, 1985;Hruby et al, 1990). In the set of peptides listed in Figure 3, amino acid residues were added at either end in order to flank cysteine and penicillamine moieties in an effort to further restrain peptide conformation.…”

A Role for Protein Kinase C-Dependent Upregulation of Adrenomedullin in the Development of Morphine Tolerance in Male Rats

“…The observations that morphine increased the number of AM-IRpositive neurons by 22-36% but AM content by 208% in DRGs suggest that AM content in individual AM neuron was also increased. Similarly, an in vitro study showed that sustained exposure to morphine concentration-dependently increased AM level in cultured ganglion explants, an effect suppressed by the selective -opioid receptor antagonist CTAP (Pelton et al, 1985), whereas another selective -opioid receptor agonist, fentanyl, also upregulated AM synthesis. The finding that the morphineinduced increase in AM level is mediated through the activation of -opioid receptors is consistent with the purported role of this receptor subtype in the development of tolerance (Taylor and Fleming, 2001;Martini and Whistler, 2007).…”