HSF-1 regulators DDL-1/2 link insulin-like signaling to heat-shock responses and modulation of longevity.

Extended longevity is often correlated with increased resistance against various stressors. Insulin/IGF-1-like signaling (IIS) is known to have a conserved role in aging and cellular mechanisms against stress. In C.

The role of backbone conformation in deltorphin II binding: a QSAR study of new analogues modified in the 5-, 6-positions of the address domain.

The delta selectivity of the opioid heptapeptides deltorphin I and II has been attributed to the C-terminal 'address' domain, the hydrophobic Val(5)-Val(6) residues apparently playing a topographical role. We now report the synthesis, opioid binding affinities, and a QSAR study of a series of peptides in which one of the valine side chains was altered. QSAR analyses included previously published models for a binding pocket interaction and an optimum size (Schullery, S.

Binding to delta and mu opioid receptors by deltorphin I/II analogues modified at the Phe3 and Asp4/Glu4 side chains: a report of 32 new analogues and a QSAR study.

The synthesis and binding affinities of 32 X3Gly4 dual-substitution analogues of the natural opioid heptapeptides deltorphin I and II are reported. A multiple regression QSAR analysis was performed using those results along with literature data for the X3Asp4 and Phe3X4 side chain analogues. Fitting to a three-term potential well model with hydrophobic and van der Waals attraction terms and a steric repulsion term indicates that the delta and mu receptor sites for binding the residue three side chain are similar, and that the binding interaction is primarily van der Waals and secondarily hydrophobic.

Opioid receptor binding requirements for the delta-selective peptide deltorphin. I: Phe3 replacement with ring-substituted and heterocyclic amino acids.

In order to assess steric, lipophilic, and electronic influences on opioid binding affinity, analogs of the delta receptor selective peptide deltorphin I (Tyr-D-Ala-Phe-Asp-Val-Val-GlyNH2) were prepared in which the residue 3 phenylalanine was replaced with lipophilic fluoro- and methyl-substituted phenylalanines or with the heterocyclic aromatic amino acids 3-(4-thiazolyl)alanine, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, histidine, and 3-(4-thiazolyl)alanine. mu binding was variable, with KiS in excess of 10,000 nM for most analogs, and all of the analogs bound poorly to k receptors. Among the phenyl ring-substituted analogs, those containing the smaller and electron-withdrawing halogens were favored over those with larger, electron-releasing methyl groups, although delta opioid binding affinity was reduced in all cases.

Development of a model for the delta opioid receptor pharmacophore. 2. Conformationally restricted Phe3 replacements in the cyclic delta receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13).

The in vitro pharmacological properties and conformational features of analogs of the delta opioid receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) in which the Phe3 residue was replaced by each of the four stereoisomers of beta-methylphenylalanine (beta-MePhe) were investigated. Both analogs in which the alpha carbon of the Phe3 replacement has L-stereochemistry display high affinity for delta receptors with the (2S,3S)-MePhe3 analog exhibiting approximately 8-fold higher affinity than the (2S,3R)-MePhe3 diastereomer. Surprisingly, one analog with D-stereochemistry in residue 3, the (2R,3R)-MePhe3 analog, also displays high affinity for the delta receptor and is extraordinarily selective for this receptor.

Development of a model for the delta opioid receptor pharmacophore. 1. Conformationally restricted Tyr1 replacements in the cyclic delta receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13).

A series of analogues of the conformationally restricted delta opioid receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM 13) was prepared in which the conformationally labile Tyr residue was replaced with several less flexible tyrosine analogues. Among these tyrosine analogues were the bicyclic structures 1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (HO-Tic), 2-amino-6-hydroxytetralin-2-carboxylic acid (Hat), and 2-amino-5-hydroxyindan-2-carboxylic acid (Hai) in which rotations about the C alpha-C beta and C beta-C gamma bonds are restricted due to cyclization of the side chain to the backbone. Also examined were analogues in which tyrosine was replaced with either trans-3-(4'-hydroxyphenyl)proline (t-Hpp) or cis-3-(4'-hydroxyphenyl)proline (c-Hpp), residues in which rotations about C alpha-C beta, but not C beta-C gamma, are restricted.

Substitution of aromatic and nonaromatic amino acids for the Phe3 residue in the delta-selective opioid peptide deltorphin I: effects on binding affinity and selectivity.

Deltorphins I and II (Tyr-D-Ala-Phe-Asp-Val-Val-Gly NH2 and Tyr-D-Ala-Phe-Glu-Val-Val-Gly NH2) display a high degree of delta-opioid receptor selectivity. Since they lack the intervening Gly3 residue found between the Tyr and Phe aromatic moieties in pentapeptide enkephalins, deltorphins I and II resemble a previously described series of cyclic tetrapeptides based on Tyr-c[D-Cys-Phe-D-Pen] (JOM-13). With the goal of development of structure-activity relationships for deltorphins and comparison with that of the cyclic tetrapeptides, ten analogs of deltorphin I were synthesized in which Phe3 was replaced with specific aromatic and nonaromatic amino acids with varying physicochemical properties.

Lipophilicity of opioids determined by a novel micromethod.

The lipophilicity of various mu-selective opioids was determined by measuring their distribution between n-octanol and Tris.HCl buffer, pH 7.4, by a procedure requiring submicromolar concentrations (submilligram amounts) of the compounds.

Tetrachlorodibenzo-p-dioxin alters rat hypothalamic endorphin and mu opioid receptors.

The present study was undertaken to assess if hypothalamic beta-endorphin (beta E) and/or brain mu opioid receptors are associated with 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) (50 micrograms/kg)-induced hypophagia and body weight decline in rats. Hypothalamic beta E concentrations were initially increased to 166% of controls on day 1, and then were depressed to 39% and 49% of control values on days 2 and 3, respectively. Brain mu opioid receptor number was increased 60% in TCDD-treated rats at day 3 without a change in the binding affinity.

Chronic ethanol consumption depresses hypothalamic-pituitary-adrenal function in aged rats.

In separate experiments, nine (n = 20) and fifteen (n = 12) month old rats were treated with either 6% ethanol or 12% sucrose (to balance caloric intake) in the drinking water to examine the effect of chronic ethanol consumption on the hypothalamic-pituitary-adrenal axis of aged rats. Rats were maintained on these treatment regimens for thirty days and were killed by decapitation. Blood was collected and plasma concentrations of adrenocorticotropin (ACTH) and corticosterone were determined by radioimmunoassay.