Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of two different radioligands, [125I]Leu8, D-Tryp22,Tyr25-somatostatin-28 and the stable somatostatin octapeptide analog [125I]204-090, D-Phe-Cys[125I]Tyr-D-Trp-Lys-Thr-Cys-Thr(ol), allowed to differentiate between two somatostatin receptor subpopulations in the human cortex. In homogenates, octapeptide somatostatin analogs displaced only part of the somatostatin-28 radioligand with high affinity. Autoradiography showed that the receptor subpopulation labelled with [125I]204-090, which we named SS1, was preferentially localized in layers V and VI, whereas the subpopulation having low affinity for somatostatin octapeptides (named SS2), measured with somatostatin-28 radioligand, was concentrated in the superficial cortical layers (I-IV) and particularly enriched in parts of lamina IV.
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PMID:Distinct topographical localisation of two somatostatin receptor subpopulations in the human cortex. 288 20

The effect on prolactin (PRL) secretion of acute administration of new octapeptide analogs of somatostatin (SS) with an enhanced and prolonged growth hormone inhibitory activity was investigated in rats under various pretreatment conditions with estrogen and antidopaminergic drugs. Analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121), at a dose of 5 micrograms/100 g body wt, did not decrease basal PRL levels in thiopental-anesthetized female rats, untreated or treated with estrogen benzoate (EB) (8 micrograms/rat) for 5 days. When haloperidol was used to elevate PRL level, a single injection of RC-121 inhibited PRL release in EB-pretreated female rats or untreated female and male rats. Analog D-Phe-Cys-Trp-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160), which has a potency similar to RC-121 in the tests on inhibition of GH, in a dose of 0.2 microgram/100 g body wt, did not lower the elevated PRL level induced by alpha-methyl-p-tyrosine and/or pretreatment with EB (100 micrograms/rat, 3 and 6 days before) in pentobarbital-anesthetized male rats. However, both analogs RC-121 and RC-160, in doses of 0.2 microgram/100 g body wt, decreased the PRL levels elevated by prolonged pretreatment with EB (100 micrograms/rat, twice a week for 3 weeks) in male rats. These results indicate that acute administration of these SS analogs can induce a prolonged inhibition of PRL release when PRL is acutely elevated by haloperidol or chronically elevated by 3 weeks of estrogen administration. Future additional studies are required to investigate the effects of chronic administration of these SS analogs on PRL levels.
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PMID:Inhibitory effects of somatostatin analogs on prolactin secretion in rats pretreated with estrogen or haloperidol. 288 61

A series of psi [CH2NH] pseudopeptide analogues of a potent somatostatin octapeptide analogue, H-D-Phe-Cys-Try-D-Trp-Lys-Val-Cys-Thr-NH2, were synthesized by using a newly developed solid-phase method for direct introduction of the CH2NH peptide bond isostere. Analogues were obtained in normal yields via a combination of sodium cyanoborohydride mediated reductive alkylation of resin-bound peptide amine with a tert-butoxycarbonyl amino acid aldehyde for introduction of a CH2NH bond and normal solid-phase peptide chemistry. A racemization test on a model pseudodipeptide indicated that no more than 6% racemization took place during the aldehyde preparation and alkylation steps. Analogues were examined for their ability to inhibit growth hormone release in vivo in sodium pentobarbital anesthetized rats and in vitro from cultured rat anterior pituitary cells. Analogues modified at the amide carbonyl of Cys2 and Lys5 showed the highest in vivo activity (20 and 8 times more potent than SRIF, respectively) and in vitro activity (0.17 and 0.67 times as active as SRIF). This compared to in vivo and in vitro potencies of 8000% and 100%, respectively, for the parent analogue. Modification of the other cyclic ring amide carbonyls of Tyr3, D-Trp4, and Val6 or the N- or C-terminal amide carbonyl of D-Phe1 or Cys7 gave analogues with considerably lower in vitro or in vivo potencies. The results appear to offer support for a proposed type II beta-turn solution conformation centered on the D-Trp-Lys portion of SRIF octapeptide analogues, resulting in possible hydrogen-bonding interactions between Tyr3 and Val6 and D-Phe1 and Thr8 residues in the parent peptide. These would then be disrupted by methylene replacement of the carbonyl groups with concomitant loss of biological activity as was observed.
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PMID:Solid-phase synthesis and biological properties of psi [CH2NH] pseudopeptide analogues of a highly potent somatostatin octapeptide. 288 17

Analogs of a potent octapeptide analog of somatostatin (SRIF) H-(D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-Thr(NH2) were synthesized. Aromatic substitutions for Tyr resulted in little change in inhibitory potency on growth hormone (GH) secretion in the rat. Substitutions for Val or (D)Trp resulted in analogs with diminished activity. Substitution of (D)Nal for (D)Phe increased duration of GH inhibition. Final weights of subcutaneously implanted prostate tumors (R3327) were 41% lower in rats treated with an N-terminal 4-chloro-(D)phenylalanyl analog as compared to vehicle treated controls. The analog had no effect on testicular weight or final plasma testosterone levels. SRIF analogs may represent an alternative treatment for prostate cancer that would be free of the untoward reproductive effects of other treatments (e.g. LH-RH or castration).
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PMID:Inhibition of rat prostate tumor growth by an octapeptide analog of somatostatin. 288 1

Cyclic somatostatin analogues containing the modified retro sequence of the amino acids Phe7 to Phe11 of the natural compound have been found to exhibit high activity for cytoprotection of rat hepatocytes against cell poisons such as phallotoxins and galactosamine. Cyclo(-Phe(p-NH(1-14C)Ac)-Thr-Lys(CO(p-N3)C6H4)-Trp-Phe-D-Pro), a photoreactive and radioactive analogue of one of the most active cyclohexapeptides, was synthesized by a combination of solid phase technique and classical solution peptide synthesis. This peptide labels the same proteins in rat liver cell membrane that are modified by photolysable derivatives of bile acids, phalloidin and antamanide.
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PMID:Synthesis of a cyclic retro analogue of somatostatin suitable for photoaffinity labelling. 288 43

Biological activities of highly potent octapeptide analogs of somatostatin (SS), D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) and D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121), were investigated in male rats. When analog RC-160 was administered to rats in which serum growth hormone (GH) levels were elevated by pentobarbital anesthesia, a dose-related inhibition of GH was obtained at dose range of 0.1 to 2.5 micrograms/kg. The time course of GH inhibition by RC-160, RC-121 and SS-14 was studied in rats treated with phenobarbital, morphine and chlorpromazine. Analogs RC-160 and RC-121 induced a prolonged inhibition of GH levels, in contrast to SS-14, whose effect was short-lived. The analogs suppressed the GH level for more than 2 hr, the peak inhibition being seen 30 to 60 min after the injection. The effects of analogs RC-160 and RC-121 on insulin secretion were observed in rats, in which insulin levels had been elevated by intravenous administration of glucose (500 mg/rat). Administration of RC-160 suppressed insulin secretion, dose-dependently, maximum but not complete inhibition being achieved at a dose of 100 micrograms/kg. In this model, RC-160 and RC-121, in doses of 30 micrograms/kg, induced a similar inhibition of insulin release as 200 micrograms/kg of SS-14, whose action of SS-14 was transient. The effect of analog RC-160 on glucagon release was studied in rats with glucagon levels elevated by hypoglycemia. RC-160 suppressed the secretion of glucagon, the inhibition being dose-dependent in the range of 0.1 to 2 micrograms/kg. Doses of 2 and 10 micrograms/kg of this analog completely suppressed the hypoglycemia-induced glucagon release. These results indicate that analogs RC-160 and RC-121 possess prolonged and enhanced biological activities, the former analog showing a high selectivity in inhibiting GH and glucagon release in vivo as compared with that of insulin secretion.
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PMID:Effects of highly potent octapeptide analogs of somatostatin on growth hormone, insulin and glucagon release. 288 86

The products and an intermediate of preprosomatostatin-II processing in the anglerfish islet were purified and subjected to structural analysis. The peptides isolated identify the site of signal cleavage (between Ser-24 and Gln-25). The prohormone is further processed at Arg-97 and, to a lesser extent, at the two adjacent basic amino acid residues Lys-61 and Arg-62. A 28-residue somatostatin is also generated which can be hydroxylated at Lys-23. A proteolytic processing site which would form the 14-residue somatostatin does not appear to be used to a significant degree. Fast atom bombardment mass spectrometry (FABMS) was used to demonstrate that the amino-terminal residues of peptides 25-60, and 25-90 are pyroglutamic acid, a modification which precludes Edman degradation of these peptides. Analysis of the peptides and tryptic peptide maps by FABMS allowed confirmation of the sites of prohormone conversion and indicated that terminal basic residues were removed during processing. Three amino acid residues were also found to differ from the amino acid sequence deduced from the cDNA and were localized to specific regions by FABMS analysis. Residues found to differ from the cDNA (cDNA in parentheses) were: Asp-77 (Thr), Val-78 (Phe), and Gly-90 (Glu). Mass assignments were confirmed by running a single cycle of Edman degradation prior to FABMS. The peptides noted above were also examined by Edman sequence analysis. The sequence of a cDNA clone to preprosomatostatin-II was re-examined in light of the observed differences at the protein level. This study emphasizes the utility of FABMS in prohormone processing studies and in identification of post-translational processing events.
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PMID:Post-translational processing of preprosomatostatin-II examined using fast atom bombardment mass spectrometry. 288 72

The agonist, and opioid antagonist, effects of intracerebroventricularly (ICV) given D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP), a cyclic analogue of somatostatin octapeptide, were evaluated using the micturition reflex of the anesthetized rat as the endpoint. Antagonist effects were evaluated against equieffective doses of selective mu [D-Ala2,NMPhe4,Gly-ol]enkephalin (DAGO) and delta [D-Pen2,D-Pen5] enkephalin (DPDPE) opioid agonists. At low ICV doses, CTP preferentially antagonized DPDPE rather than DAGO; increasing the dose of CTP further effectively antagonized both mu and delta agonists, while even higher doses showed an agonist effect alone which was not blocked by adrenergic, cholinergic or opioid antagonists. Selective opioid antagonist doses of CTP failed to block the inhibition of the micturition reflex produced by pentobarbital. Possible residual somatostatin like properties of CTP were tested by using somatostatin as a possible antagonist of equieffective doses of DPDPE and DAGO; somatostatin did not antagonize these agonists. Repeated exposure to CTP resulted in the development of acute tolerance to the agonist effect, and also prevented the inhibition of the reflex by high doses of somatostatin, with the converse experiment showing a similar pattern; thus, repeated somatostatin resulted in tolerance and subsequent cross-tolerance to the agonist effects of CTP. In animals tolerant to somatostatin, CTP nevertheless behaved as an opioid antagonist. The present results indicate that CTP possesses opioid antagonist properties in vivo which are pharmacological in nature but nevertheless retains residual somatostatin-like activity at higher doses.
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PMID:Effects of a novel opioid peptide antagonist on rat bladder motility in vivo. 288 99

In hippocampal slices, somatostatin 14 and its stable analog L363 [cyclo(Phe-Pro-Phe-D-Trp-Lys-Thr)] fail to modify muscarinic signal transduction mediated by stimulation of phosphoinositide breakdown, whereas somatostatin 14 mimics oxotremorine in inhibiting adenylate cyclase activity of hippocampal membranes. The simultaneous addition of somatostatin 14 and oxotremorine elicits a nonadditive convergent inhibition of adenylate cyclase activity. Both L363 and oxotremorine nonadditively stimulate a high-affinity guanosine 5'-triphosphatase activity of hippocampal membranes. This stimulation could be operative in mediating the convergent inhibition of adenylate cyclase activity elicited by the binding of specific ligands to somatostatin and muscarinic recognition sites present in hippocampal membranes. Because L363 competitively displaces muscarinic agonists fand antagonists from their specific recognition sites, one might infer that the two recognition sites interact functionally; that is, somatostatin reduces the efficacy of oxotremorine and/or vice versa.
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PMID:In rat hippocampus, somatostatin 14 and muscarinic receptor ligands modulate an adenylate cyclase belonging to a common domain of the receptor. 288 75

The combination of a long-acting delivery system for the agonist [D-Trp6]luteinizing hormone-releasing hormone ([D-Trp6]LH-RH) with modern somatostatin analogs was studied in the Dunning R-3327H rat prostate cancer model. Microcapsules of [D-Trp6]LH-RH releasing 25 micrograms/day were injected once a month. In the first experiment the adjunct was the somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121), administered at a dose of 2.5 micrograms twice a day, and the therapy was continued for 70 days. Tumor volume was significantly decreased by [D-Trp6]LH-RH microcapsules or RC-121 given alone. The combination of microcapsules and analog RC-121 caused a greater inhibition of tumor growth than the single agents. Similar effects were seen when the percent increase in the tumor volume was examined. The inhibition of tumor growth caused by the [D-Trp6]LH-RH microcapsules was greater than that caused by RC-121. The combination of the two agents was again the most effective, resulting in the smallest increase in tumor volume. Tumor weights were much lower in the groups treated with microcapsules or RC-121 alone than in controls. The lowest tumor weights were obtained in the group that received the combination of [D-Trp6]LH-RH microcapsules and RC-121. Similar results were obtained in the second experiment, in which the animals were treated for a period of 83 days with microcapsules containing the somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) that released 5 micrograms/day and were injected twice a month alone or in combination with microcapsules of [D-Trp6]LH-RH. Microcapsules of analog RC-160 given alone significantly decreased tumor growth as measured by the final tumor volume, the percentage change from the initial tumor volume, and the reduction in tumor weight. The inhibition of tumor growth induced by [D-Trp6]LH-RH microcapsules was greater than that caused by RC-160. The most striking decrease in tumor weight and volume was obtained in animals treated with microcapsules of [D-Trp6]LH-RH combined with the delayed delivery system for RC-160. The overall response to the combination therapy could reflect the inhibition by somatostatin analogs of the proliferation of prostate cancer cells through a decrease in growth hormone and prolactin release and interference with endogenous growth factors, in addition to the main effect, which is the suppression by [D-Trp6]LH-RH of the growth of androgen-dependent tumor cells. Our results indicate that somatostatin analogs enhance the inhibitory effects of [D-Trp6]LH-RH on the growth of prostate tumors. The administration of somatostatin analogs in combination with microcapsules of [D-Trp6]LH-RH might improve clinical response in patients with advanced prostate carcinoma.
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PMID:Somatostatin analogs as adjuncts to agonists of luteinizing hormone-releasing hormone in the treatment of experimental prostate cancer. 289 Jan 64


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