Cyclic, disulfide- and dithioether-containing opioid tetrapeptides: Development of a ligard with high delta opioid receptor selectivity and affinity

Tetrapeptides of primary sequence Tyr-X-Phe-YNH2, where X is D-Cys or D-Pen (penicillamine) and where Y is D-Pen or L-Pen, were prepared and were cyclized via the side chain sulfurs of residues 2 and 4 to disulfide or dithioether-containing analogs. These peptides are related to previously reported penicillamine-containing pentapeptide enkephalin analogs but lack the central glycine residue of the latter and were designed to assess the effect of decreased ring size on opioid activity. Binding affinities of the tetrapeptides were determined to both [mu] and [delta] opioid receptors. Binding affinity and selectivity in the tetrapeptide series were observed to be highly dependent on primary sequence. For example, L-Pen4 analogs displayed low affinity and were nonselective, while the corresponding D-Pen4 diastereomers were of variable affinity and higher selectivity. Among the latter compounds were examples of potent analogs in which selectivity shifted from [delta] selective to [mu] selective as the ring size was increased. The relatively high binding affinity and [delta] receptor selectivity observed with one of the carboxamide terminal disulfide analogs led to the synthesis of the corresponding carboxylic acid terminal, Tyr-D-Cys-Phe-D-PenOH. This analog displayed [delta] receptor binding selectivity similar to that of the standard [delta] ligand, [D-Pen2, D-Pen5] enkephalin (DPDPE), and was found to have a 3.5-fold higher binding affinity than DPDPE. All the tetrapeptides were further evaluated in the isolated mouse vas deferens (mvd) assay and all displayed opioid agonist activity. In general, tetrapeptide potencies in the mouse vas deferens correlated well with binding affinities but were somewhat lower. Receptor selectivity in the mvd, assessed by examining the effect of opioid antagonists on the tetrapeptide concentration-effect curves, was similar to that determined in the binding studies.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27602/1/0000646.pd

Pharmacophore elements of the TIPP class of delta opioid receptor antagonists

A series of tri-and tetrapeptides sharing the amino-terminal dipeptide unit Tyr-Tic, found in the high-affinity delta opioid receptor antagonist Tyr-Tic-Phe-Phe (TIPP), was prepared and evaluated in receptor binding assays to explore the role(s) of the phenylalanine residues in positions 3 and 4. It was found that aromaticity of residues 3 and 4 is not required for high affinity, a lipophilic side chain in either location being sufficient, as evidenced by the high delta receptor binding affinities observed for the tetrapeptide Tyr-Tic-Ala-Leu and the tripeptide Tyr-Tic-Leu. These results support the suggestion of Temussi et al. [Biochem. Biophys. Res. Commun., 198 (1994) 933] that the aromatic side chain of the Tic residue corresponds to the aromatic side chain found in residues 3 or 4 in other delta-selective peptide series.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43172/1/10989_2004_Article_BF00126275.pd

Pharmacological characterization of [D-Ala2,Leu5,Ser6]enkephalin (DALES): antinociceptive actions at the [delta]non-complexed-opioid receptor

Substantial evidence has been accumulated which suggests that opioid [delta] receptors may be distinguished on the basis of their involvement in the modulation (i.e., increase or decrease in potency) of [mu]-mediated antinociception. On this basis, it has been hypothesized that some opioid [delta] receptors exist within a functional complex with [mu] receptors ([delta]complexed ([delta]cx) receptors) while other [delta] sites do not ([delta]non-complexed ([delta]ncx) receptors). Recent work with [D-Ala2,Leu5,Cys6]enkephalin (DALCE) has demonstrated that this compound produces initial antinociceptive actions, does not modulate morphine antinociception and appears to bind irreversibly to the [delta]ncx site, presumably by means of thiol-disulfide exchange between the receptor and the cysteine sulfhydryl group. To determine if a structural basis exists for actions at the hypothesized [delta]ncx receptor, in the present study we report the synthesis and pharmacological characterization of [D-Ala2,Leu5,Ser6]enkephalin (DALES), a close structural analogue of DALCE. If a structural basis for action at the [delta]ncx site exists, then DALES would be predicted to produce antinociception, fail to modulate morphine antinociception and, since it lacks the free sulfhydryl group present in DALCE, fail to exhibit irreversible antagonistic actions; these predictions were supported. Additionally, pretreatment with DALCE at - 24 h, but not with DALES, blocked DALES-induced antinociception. These observations in vivo support the concept of a structural basis for activity at the hypothesized [delta]ncx site and suggest that DALES, like DALCE, may be a useful probe for pharmacological characterization of putative [delta] receptor subtypes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29502/1/0000588.pd

Opioid receptor affinity and selectivity effects of second residue and carboxy terminal residue variation in a cyclic disulfide-containing opioid tetrapeptide

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74202/1/j.1399-3011.1991.tb00274.x.pd