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.