| 2886635 |
Mu opioid antagonist properties of a cyclic somatostatin octapeptide in vivo: identification of mu receptor-related functions |
None |
J Pharmacol Exp Ther |
Mu opioid antagonist properties of a cyclic somatostatin octapeptide in vivo: identification of mu receptor-related functions
Abstract
- We have shown previously that D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP) produces selective antagonism of mu, but not delta or kappa, opioid receptor-selective ligands in the guinea pig ileum and mouse vas deferens bioassays, and in radioligand binding assays using homogenized rat brains. In the present study we characterized the agonist and opioid antagonist profile of CTP in analgesic (hot-plate test, abdominal stretch test) and in gastrointestinal assays (transit time test) in mice. CTP was a potent antagonist of the supraspinal and spinal analgesic effects of the mu selective agonist MePhe3, D-Pro4morphiceptin (PL017) in both assays. The gastrointestinal antitransit actions of PL017 were also antagonized by CTP at both supraspinal and spinal sites. CTP did not alter the effects of the kappa agonist trans-3,4-dichloro-N-methyl-N-(2-(1-pyrolidinyl)cyclohexyl)benz eneacetamine in any test. Surprisingly, CTP also antagonized the analgesia produced by i.c.v. and intrathecal administration of D-Pen2, D-Pen5enkephalin (DPDPE), a highly delta selective agonist, in both analgesic tests. Differential antagonism of DPDPE, but not PL017, by the delta selective antagonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH in the hot-plate test indicates that PL017 and DPDPE may act at separate receptors to produce analgesia (mu and delta, respectively). In contrast, CTP did not reverse the gastrointestinal antitransit effects of intrathecal DPDPE. Schild analysis of the interactions of CTP with supraspinal mu and delta agonists in the hot-plate test indicated that although CTP antagonized PL017 in a competitive fashion (Schild slope = -1.0), the interaction of CTP with DPDPE was not competitive (Schild slope = -0.5).(ABSTRACT TRUNCATED AT 250 WORDS)
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| 2888099 |
Effects of a novel opioid peptide antagonist on rat bladder motility in vivo |
10.1016/0196-9781(87)90036-2. |
Peptides |
Effects of a novel opioid peptide antagonist on rat bladder motility in vivo
Abstract
- 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-olenkephalin (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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| 2889824 |
Analysis of structural requirements for the absorption of drugs and macromolecules from the nasal cavity |
10.1002/jps.2600760709. |
J Pharm Sci |
Analysis of structural requirements for the absorption of drugs and macromolecules from the nasal cavity
Abstract
- An octapeptide and a protein, of molecular weights 800 and 34,000, respectively, were found to have nasal bioavailabilities of 73 and 0.6%, respectively, in the rat. This data, combined with reported values for 23 other compounds, indicated good availability without adjuvants for all molecules up to 1000 molecular weight (mean 70%, SD between compounds 26%, n = 15) with a decline in availability above this value. The relationship between absorption and molecular weight was modeled assuming competition between constant clearance from the nasal cavity and molecular weight-dependent transport through the mucosa. Deviations of absorption from values predicted by this model did not correlate with factors such as charge, hydrophobicity, or susceptibility to aminopeptidases, but the relative absorption of cyclic and cross-linked peptides and proteins was significantly greater than that of linear peptides. It is argued that the most likely route for transport is through junctions between cells and that surface-active adjuvants (MW 6000) which markedly enhance insulin uptake may act by rendering hydrophobic areas of contact of the junctional proteins temporarily hydrophilic. The nasal route is suitable for efficient, rapid delivery of many molecules of molecular weight less than 1000. With the use of adjuvants, this limit can be extended to at least 6000 and possibly much higher.
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| 2893264 |
H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2: a potent and selective antagonist opioid receptors |
None |
NIDA Res Monogr |
H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2: a potent and selective antagonist opioid receptors
Abstract
- H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) exhibited high affinity (IC50 = 2.80 nM) in displacing 3Hnaloxone binding (nH = 0.89 +/- 0.1) and showed an exceptional selectivity for mu opioid receptors with an IC50(DPDPE)/IC50(naloxone) ratio of 4,840, while it displayed very low affinity for somatostatin receptors (IC50 = 22,700 nM) in rat brain binding assays. 3HCTOP was recently custom synthesized (spec. act.: 84 Ci/mmol) and evaluated for its in vitro binding properties towards the mu opioid receptors in rat brain membrane preparations. Association and dissociation of 3HCTOP binding to mu opioid receptors were rapid at 25 degrees C with a kinetic Kd value of 0.67 nM. Saturation experiments gave apparent Kd value of 1.11 nM and Bmax value of 136 +/- 13 fmol/mg prot at 25 degrees C. Specific 3HCTOP binding was inhibited by a number of different opioid and opiate ligands. Among them, putative mu opioid receptor-specific ligands, such as naloxone, naltrexone and CTOP inhibited the binding with high affinity, while delta opioid receptor-specific compounds or non-opioid drugs inhibited specific 3HCTOP binding with low affinity or they were ineffective.
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| 2893363 |
Somatostatin and its analog enhance the formation of human leukocyte migration inhibiting factor: further evidence for immunomodulatory action of somatostatin |
10.1016/0196-9781(87)90087-8. |
Peptides |
Somatostatin and its analog enhance the formation of human leukocyte migration inhibiting factor: further evidence for immunomodulatory action of somatostatin
Abstract
- The effect of somatostatin-14 (SST) and somatostatin analog D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2 (RC-102) on migration inhibition of human leukocytes induced by cardiac antigen or phytohemagglutinin (PHA) was investigated. Both SST and RC-102 augmented the migration inhibition, thus indicating the enhanced formation or action of the leukocyte migration inhibiting factor (LMIF). This finding provides additional evidence for the immunomodulatory action of somatostatin.
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| 2893981 |
A cyclic somatostatin analog that precipitates withdrawal in morphine-dependent mice |
None |
NIDA Res Monogr |
A cyclic somatostatin analog that precipitates withdrawal in morphine-dependent mice
Abstract
- We evaluated the ability of the mu selective, peptidic, opioid antagonist CTP to precipitate withdrawal in morphine-dependent mice after intracerebroventricular (i.c.v.) and subcutaneous (s.c.) administration. The withdrawal syndrome evoked by i.c.v. CTP was different in some respects from that observed after i.c.v. naloxone. Naloxone, given i.c.v., produced shakes and tremors, defecation, diarrhea, wet dog shakes, jumping and weight loss. In contrast, the prominent signs following i.c.v. CTP were grooming, tremors and shakes, defecation, wet dog shakes and weight loss. CTP treated mice exhibited a greatly reduced incidence of jumping behaviors and diarrhea. While s.c. naloxone evoked similar effects to i.c.v. naloxone, CTP given s.c. stimulated defecation and modest weight loss only. The differences in the profile of withdrawal signs between naloxone and CTP may be related to their differences in receptor selectivity or possibly to their respective alkaloidal and peptidic natures. The relative lack of behavioral effects seen after s.c. CTP probably reflects the inability of CTP to pass through the blood brain barrier, and indicates that although the majority of withdrawal signs are mediated by centrally located opioid receptors, the gastrointestinal tract can be withdrawn independently of the central nervous system.
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| 2897854 |
In vitro and in vivo inhibition of human small cell lung carcinoma (NCI-H69) growth by a somatostatin analogue |
10.1016/s0006-291x(88)81192-6. |
Biochem Biophys Res Commun |
In vitro and in vivo inhibition of human small cell lung carcinoma (NCI-H69) growth by a somatostatin analogue
Abstract
- An endocrinologically-potent octapeptide analogue of somatostatin (SRIF), 3-(2-naphthyl)-D-Ala-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (BIM-23014 C), was examined for its ability to inhibit the in vitro and in vivo growth of the human small cell lung carcinoma (SCLC) line, NCI-H69. When cultured cells were implanted into athymic nude mice, treatment (500 micrograms/injection, twice daily) resulted in a prolongation of lag time for the appearance of measurable tumors, and there was a marked inhibition of the growth rate. Indeed, peptide injection in the region of the tumor resulted in a complete regression of the NCI-H69 tumors. Withdrawal of BIM-23014 C treatment resulted in an acceleration of tumor growth indicating an antiproliferative rather the oncolytic action. A similar inhibition of tumor growth was also observed when solid tumors obtained from the first implantation were used as the donor tissues. In cell culture, the proliferation in the presence of a low concentration (10nM) of BIM-23104 C was also significantly retarded suggesting a direct mechanism of action.
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| 2898868 |
Effects of neurohypophyseal hormones on food-reinforced classical conditioning in the rat |
None |
Acta Physiol Hung |
Effects of neurohypophyseal hormones on food-reinforced classical conditioning in the rat
Abstract
- The effects of different doses of lysine vasopressin (LVP) and oxytocin (OXT) were studied on the six-day acquisition or extinction of a food-reinforced classical conditioning reflex (conditional stimulus: light) when intraperitoneal (ip.) injections were carried out 20 min prior to the behavioural sessions. The highest (600 mU/kg) dose of LVP inhibited acquisition, and all LVP doses tested (150, 300 and 600 mU/kg) facilitated the extinction of conditioned behaviour. These same mU doses of OXT did not significantly affect the food-reinforced conditioning, although a consequent tendency towards increased performance (the opposite action to vasopressin) was observed. When 2.5 or 25 micrograms/kg doses of desglycinamide-arginine-vasopressin (DGAVP), a 500 micrograms/kg dose of prolyl-leucyl-glycinamide (PLG) or a 1200 mU/kg dose of OXT was injected during the extinction sessions, 2.5 micrograms/kg DGAVP and 1200 mU/kg OXT significantly facilitated extinction; the other treatments were without effect. LVP in a dose of 300 or 600 mU/kg and OXT in a dose of 300, 600 or 1200 mU/kg did not influence the food intake of 22 h food-deprived rats in a nonconditional situation. The present results indicate that the effects of LVP and OXT on memory display reinforcement-dependent characteristics, and are thus indirect or non-specific in nature.
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| 2907513 |
Peptide conformations--49(1): synthesis and structure-activity relationships of side chain modified peptides of cyclo(-D-Pro-Phe-Thr-Lys-Trp-Phe.) |
10.1111/j.1399-3011.1988.tb00933.x. |
Int J Pept Protein Res |
Peptide conformations--49(1): synthesis and structure-activity relationships of side chain modified peptides of cyclo(-D-Pro-Phe-Thr-Lys-Trp-Phe.)
Abstract
- Cyclic hexapeptide analogues representing the modified retro sequence of the amino acid residues 7-11 of natural somatostatin are known to protect liver cells from phalloidin poisoning. To determine the influence of steric, lipophilic, and charge effects on (a) the conformation of the backbone and the aromatic side chains and (b) the biological response, the side chains of Phe2, Lys4, and Phe6 of cyclo(-D-Pro1-Phe2-Thr3-Lys(Z)4-Trp5-Phe6-), 1a, one of the most active peptides found so far, were modified by various residues. The discussion of conformationally relevant parameters proves that neither backbone conformations nor populations of aromatic side chain rotamers were altered by these substitutions. The potency of these derivatives in a cytoprotection assay varies by at most one order of magnitude (more or less active than the parent peptide 1a). A qualitative evaluation of lipophilic, steric, and charge effects reveals the dominance of lipophilic effects of aromatic residues; the most potent compounds contain aromatic substructures in the side chain of Lys4.
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| 2920728 |
Purification and properties of five different forms of human procarboxypeptidases |
10.1111/j.1432-1033.1989.tb14590.x. |
Eur J Biochem |
Purification and properties of five different forms of human procarboxypeptidases
Abstract
- Three different procarboxypeptidases A and two different procarboxypeptidases B have been isolated for the first time, in a pure and native state, from human pancreatic extracts. These proteins were purified in one or two quick steps by anion-exchange HPLC. All these forms have been biochemically characterized. Two of the procarboxypeptidases A, the A1 and A2 forms, are obtained in a monomeric state while the other, the A3 form, is obtained as a binary complex of a procarboxypeptidase A with a proproteinase E. This complex is stable in aqueous buffers at various ionic strengths and develops carboxypeptidase A and proteinase E activities in the presence of trypsin. The A1 and A2 forms show clear differences in electrophoretic mobility in SDS/polyacrylamide gels, isoelectric point, proteolytic activation process with trypsin and susceptibility to thermal denaturation. In contrast, these properties are similar in the A1 and A3 (binary complex) forms. On the other hand, with respect to the properties listed above, the B1 and B2 forms differ from each other mainly in isoelectric point. An overall comparison of the above properties reveals the unusual character of the A2 form, midway between the other A and B forms. N-terminal extended sequence analysis carried out on these proenzymes confirm that they constitute different isologous forms.
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| 2934378 |
Inhibitory effect of the partially resolved coordination isomers of chromic desferricoprogen on coprogen uptake in Neurospora crassa |
10.1128/jb.165.1.283-287.1986. |
J Bacteriol |
Inhibitory effect of the partially resolved coordination isomers of chromic desferricoprogen on coprogen uptake in Neurospora crassa
Abstract
- Two partially resolved chromatographic fractions of geometrical and optical isomers of the chromic complexes of desferricoprogen, a siderophore from Neurospora crassa, were obtained from high-pressure liquid chromatography on a reverse-phase matrix. The first fraction was identified as a cis complex with a 20% diastereomeric excess of the lambda isomer. The second fraction was identified as a mixture of several of the possible trans isomers with a net 20% diastereomeric excess of the delta isomers. These fractions were used to evaluate the stereospecificity of the coprogen-mediated iron uptake system with respect to the metal coordination center. Fraction II competitively inhibited coprogen uptake, whereas fraction I showed only slight inhibition. N. crassa accumulated chromium from fraction II faster than the rate of chromium uptake from fraction I. Neither fraction had a significant effect on the uptake of ferricrocin, suggesting that coprogen and ferricrocin are taken up by different receptor systems.
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| 2952235 |
In vivo simultaneous comparison of pressor and uterine responses to a single agonist (oxypressin) in estrous rats |
10.1139/y87-002. |
Can J Physiol Pharmacol |
In vivo simultaneous comparison of pressor and uterine responses to a single agonist (oxypressin) in estrous rats
Abstract
- To try to compare receptor compartment kinetics, receptor binding, and binding-response coupling for two smooth muscle types in vivo, pressor and uterine responses to oxypressin, an equipotent analog of oxytocin and vasopressin, were studied simultaneously in urethane-anesthetized, pentolinium-indomethacin treated rats. Access of peptide to the pressor and uterine receptor compartments and peptide-receptor dissociation rate had a negligible effect on the two responses. During both injections and infusions, the blood pressure response seemed to be determined largely by plasma levels of oxypressin. The uterine response to oxypressin, however, was paradoxical. The heights of individual uterine contractions seemed to be determined throughout by plasma oxypressin concentrations. The interval between contractions also seemed to be determined by plasma peptide concentrations during injections. However, as plasma peptide increased and reached steady state during infusion, contraction interval behaved as if plasma peptide concentrations were decreasing. This effect was more marked at the beginning of infusion. The implication of these results is that binding determines the pressor response to oxypressin and binding-response coupling does not change. In contrast, although binding determines the uterine response to oxypressin during injection and binding-response coupling appears constant, some factor in addition to binding affects the contraction interval portion of the uterine response and modifies the apparent binding-response coupling of this parameter during infusion.
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| 2954418 |
Effects of L-valyl-valine anhydride on the blood-perfused canine sinoatrial node and papillary muscle |
None |
Zhongguo Yao Li Xue Bao |
Effects of L-valyl-valine anhydride on the blood-perfused canine sinoatrial node and papillary muscle
Abstract
|
| 2965181 |
Arginine vasopressin (AVP) replacement of helper cell requirement in IFN-gamma production. Evidence for a novel AVP receptor on mouse lymphocytes |
None |
J Immunol |
Arginine vasopressin (AVP) replacement of helper cell requirement in IFN-gamma production. Evidence for a novel AVP receptor on mouse lymphocytes
Abstract
- Arginine vasopressin (AVP), a nine-amino acid neurohypophyseal hormone, is capable of replacing the helper cell requirement for IFN-gamma production by Lyt-2+ mouse splenic lymphocytes. We present data here showing that the AVP helper signal occurs via interaction with a novel R on splenic lymphocytes and involves primarily the N-terminal six-amino acid cyclic ring (pressinoic acid) with the C-terminal three-amino acid end of AVP playing a minor role. Pressinoic acid was capable of providing help at concentrations similar to those of AVP, whereas oxytocin and isoleucine pressinoic acid were 10- and 100-fold less effective, respectively. Isoleucine pressinoic acid has the same structure as pressinoic acid except for the substitution of isoleucine for phenylalanine in position 3 of the sequence. Consistent with the function data, R binding competitions with splenic lymphocyte membrane preparations showed that AVP and pressinoic acid competed similarly with 3HAVP, whereas oxytocin and isoleucine pressinoic acid were much less effective competitors. Further characterization of the AVP lymphocyte R was performed using AVP analogues having well defined agonist and antagonist activities on either V1 (vasopressor) R or V2 (antidiuretic) R. The AVP helper signal was blocked by the V1 antagonist d(CH2)1(5) Tyr(methyl)AVP but not by another V1 antagonist, d(CH2)1(5)D-Tyr(ethyl)2Val4AVP. Both V1-R antagonists were able to block 3HAVP binding to the V1-R on liver cells, whereas only the V1 antagonist that blocked AVP help was able to compete effectively for the spleen AVP-R. Neither a V2 agonist nor a V2 antagonist had any effect on AVP help in IFN-gamma production. These data strongly indicate the presence of a novel AVP-R on spleen lymphocytes, which is related to the classic V1-R on liver cell membranes.
|
| 2981179 |
tRNA binding to programmed ribosomes increases the ribosomal affinity for tuberactinomycin O |
10.1016/0014-5793(85)80186-1. |
FEBS Lett |
tRNA binding to programmed ribosomes increases the ribosomal affinity for tuberactinomycin O
Abstract
- The binding of 14C-labelled tuberactinomycin O was analysed in equilibrium dialysis cells. The ionic conditions and the concentration of the labelled drug used in the binding assays allowed the binding of just one drug molecule per non-programmed ribosome. Under these conditions, the occupation of the ribosomal P-site by deacylated tRNAPhe in the presence of poly(U) increased the amount of 14Ctuberactinomycin O bound by a factor of two. Kanamycin, gentamicin and neomycin reduced the binding of tuberactinomycin O, whereas chloramphenicol, tetracycline, streptomycin and puromycin had no effect. A stimulation of the binding of tuberactinomycin O was found upon addition of erythromycin.
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