Analogs of the 29 amino acid sequence of human growth hormone-releasing hormone (hGH-RH) with agmatine (Agm) in position 29, desaminotyrosine (Dat) The wide availability of human growth hormone (GH) produced by recombinant DNA methods has made possible the treatment of GH-deficient patients. However, in most of the cases, GH insufficiency, both in children and in elderly subjects, is due to changes in the control of GH secretion by the hypothalamus, rather than to the decrease in somatotroph response caused by an impairment at the pituitary level (1). Thus, an alternative form of therapy based on the human hypothalamic growth hormonereleasing hormone (hGH-RH-) that stimulates GH secretion could also be used. It has been demonstrated that hGH-RH-(1-44), hGH-RH-(1-40), and the shortened fragment, hGH-RH-(1-29)-NH2, accelerate growth velocity in GH-deficient children (1-5). It has also been shown that prolonged administration of hGH-RH does not cause somatotroph desensitization or depletion in normal men (6). Short-term s.c. administration of GH-RH to healthy men over 60 years old reverses age-related decreases in GH and insulin-like growth factor I (7), suggesting that prolonged treatment could improve age-related alteration in the body, as well as the health, strength, and functional capacity in an aging population, as demonstrated by Rudman with GH (8). GH-RH treatment does not cause hypertension, which has been observed during treatment with GH when excess hormone was used (7).The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.Although usefulness of hGH-RH-(1-44) and hGH-RH-(1-29)-NH2 for medical applications has been demonstrated, there is still a great demand for more stable analogs which would allow a reduction in the doses and frequency of administration. Examination of enzymatic degradation in serum and homogenates of liver, pituitary, and hypothalamus indicates that hGH-RH-(1-44) and its shortened fragment are rapidly metabolized, and the resulting products are not biologically active (9). The major cleavage site in plasma is the bond between amino acids 2 and 3 (dipeptidylpeptidase cleavage site) (10, 11). In homogenates of pituitary and hypothalamus, the major cleavage sites are the Leu14-Gly15 and Tyr10-Argtl bonds (chymotrypsin-like cleavage sites) and the Lys21-Leu22 bond (trypsin-like cleavage site) (12). All GH-RH fragments produced by trypsin cleavage are biologically inactive (9).Numerous analogs of GH-RH were synthesized in various laboratories to obtain compounds of improved metabolic stability and increased potency (9,(13)(14)(15)(16)(17)(18)(19). Several modifications have been proposed to increase resistance of the peptides to the degradation from the N and C termini.The GH-RH molecule is unique among biologically active peptides in the sense that it contains two pairs of basic amino acids. It would be expected for this sequen...
Six novel cyclic enkephalin analogues have been synthesized. Cyclization of the linear peptides containing basic amino acid residues in position 2 and 5 was achieved by treatment with bis(4-nitrophenyl)carbonate. It was found that some of the compounds exibit unusually high mu-opioid activity in the guinea pig ileum (GPI) assay. The 18-membered analogue cyclo(N(epsilon),N(beta)-carbonyl-D-Lys2,Dap5)-enkephalinamide turned out to be one of the most potent mu-agonists reported so far. NMR spectra of the peptides were recorded and structural parameters were determined. The conformational space was exhaustively examined for each of them using the electrostatically driven Monte Carlo method. Each peptide was finally described as an ensemble of conformations. A model of the bioactive conformation of this class of opioid peptides was proposed.
The aim of this study was to investigate whether the δ-opioid receptors are involved in the rewarding and reinstatement effect of cocaine in the conditioned place preference (CPP) test. Male Wistar rats were conditioned with cocaine (5 mg/kg) or saline in a biased CPP procedure. The intracerebroventricular (i.c.v.) administration of naltrindole (5 nmol), δ-opioid receptor antagonist but not β-funaltrexamine (5 nmol), or nor-binaltorphimine (10 nmol), μ-opioid and κ-opioid receptor antagonists, respectively reversed the expression of the cocaine CPP. The i.c.v. administration of new analogues of deltorphins with potent agonist activity at δ-opioid receptors, such as cyclo(N, N-carbonyl-D-Orn, Orn)deltorphin (DEL-6) at the dose of 10 and 20 nmol and deltorphin II N-(ureidoethyl)amide (DK-4) at the dose of 10 and 20 nmol reinstated the rewarding effect of cocaine after extinction sessions in the CPP test. Naltrindole (5 nmol, i.c.v.) abolished the reinstated effect of DK-4 (10 nmol). In addition, DEL-6 and DK-4 induce anxiolytic-like effects in the elevated plus-maze test. However, neither peptide given alone either produced a rewarding effect in the CPP test, or influenced the locomotor activity and motor coordination, thus suggesting that these effects of peptides did not influence the results obtained in the reinstatement procedure of CPP. In conclusion, our results show that δ-opioid receptors play a dominant role in cocaine reward and reinstatement of cocaine seeking behavior in the CPP test.
Stendomycin, an antifungal peptide antibiotic, is a mixture of closely related compounds. Their amino acid sequence was elucidated mainly through the study of peptides from partial acid hydrolysates. In all members of the stendomycin family the N-terminal amino acid, proline, is acylated by a branched-chain fatty acid; the C-terminal amino acid, a cyclic derivative of arginine, forms a lactone bond with the hydroxyl group of one of the allothreonine residues. The configurations of the amino acid components and conformational aspects of the whole antibiotic are also discussed.he antifungal antibiotic stendomycin was isolated T from cultures of Streptomyces endus by Thompson and Hughes' in the Lilly Research Laboratories. These investigators described some physical and chemical properties of stendomycin, recognized its peptide nature, and identified several of the amino acid constituents. A generous sample from Eli Lilly and Co., Indianapolis, Ind., allowed us to elucidate the structure of stendomycin.In the first report on stendomycinl two varieties of the antibiotic were described, stendomycin A and stendomycin B. These were separated by countercurrent distribution. In our experiments the same separation of two major peaks could be observed. However, the two products from the countercurrent distribution showed the same mobility on thin layer chromatograms and were indistinguishable from each other by amino acid analysis, uv, ir, and nmr spectra, and the ratio of their fatty acid constituents. Therefore, it was assumed that the difference between the two species, A and B, might be in the anion that is paired with the single but strong cationic center of the molecule. This assumption was supported by observations made on thin layer chromatograms of the antibiotic. In the solvent systems containing an excess of an acid, such as acetic acid, only a single spot was revealed.These observations would suggest that stendomycin is a single entity. Yet, when acid hydrolysates of stendomycin were extracted with an organic solvent such as ether or hexane, a mixture of five different fatty acids3 was obtained. Since the molecule of the antibiotic contains only 1 mol of fatty acid, it became obvious that we were dealing with a family of closely related compounds; each member of the group contains a different fatty acid. Soon afterwards it was found that some of the amino acid constituents4 are (1) R. Q. Thompson and M.
A new family of cyclic opioid peptide analogues related to the 1-4 sequence of dermorphin/deltorphin (Tyr-D-Aaa2-Phe-Aaa4-NH2) has been synthesized. The synthesis of the linear precursor peptides was accomplished by the solid-phase method and ring formation was achieved via a ureido group incorporating the side chain amino functions of D-Aaa2 (D-Lys, D-Orn) and Aaa4 (Lys, Orn, Dab, Dap). The peptides were tested in the guinea-pig ileum (GPI) and mouse vas deferens (MVD) assays. Most showed very high agonist potency in the GPI assay. The peptide containing D-Lys in position 2 and Dab in position 4 was 210 times more active than enkephalin, and that containing Orn and Dab, respectively, was 150 times more active than enkephalin. The latter peptide was also very active in the MVD assay, and showed an IC50 MVD/GPI ratio of 0.816. NMR spectra of selected peptides were recorded, and structural parameters were determined. The conformational space of the peptides was examined using the electrostatically driven Monte Carlo method. With the help of the NMR spectra each peptide was described as an ensemble of conformations. The conformations have been interpreted with regard to the opioid activities, and comparisons have been made with a model proposed earlier for enkephalin analogues.
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