naltrindole and tyrosyl-1-2-3-4-tetrahydro-3-isoquinolinecarbonyl-phenylalanyl-phenylalanine

It has been found that stimulation of delta-1 opioid receptors by intravenous administration of DPDPE (0.5 mg/kg) decreases the incidence of ischemic and reperfusion-induced arrhythmias and also increases myocardial tolerance to the arrhythmogenic action of epinephrine in rats. Pretreatment with a selective delta-2 agonist, DSLET, had no antiarrhythmic effect. The inhibition of the enzymatic breakdown of endogenous enkephalins by intravenous administration of acetorphan decreased the incidence of epinephrine-induced arrhythmias. Pretreatment with a selective delta opioid receptor antagonist, ICI-174.868, completely abolished this antiarrhythmic effect. Adaptation of rats to repeated immobilization stress during 12 days increased myocardial tolerance to the arrhythmogenic action of coronary artery occlusion (10 min) and reperfusion (10 min). Pretreatment with a selective delta opioid receptor antagonist, TIPP(Psy), did not abolish the antiarrhythmic effect of adaptation to immobilization stress. It seems that endogenous agonists of delta opioid receptors are not involved in the antiarrhythmic effect resulting from adaptation to stress.

Topics: Adaptation, Physiological; Animals; Arrhythmias, Cardiac; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine; Ligands; Male; Myocardial Reperfusion Injury; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Rats; Rats, Wistar; Receptors, Opioid, delta; Tetrahydroisoquinolines; Thiorphan

Bioactive models for a delta opioid receptor antagonist are proposed based on the structurally rigid, diketopiperazine containing cyclo 2',6'-dimethyl-L-tyrosyl (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic). Monte Carlo conformational analysis of c(Dmt-Tic) generated three low energy clusters (I-III) of conformers. The lowest energy conformer representing cluster I superimposed best with the X-ray crystal structures of c(Tyr-Tic), an inactive diketopiperazine with similar framework as c(Dmt-Tic), with H-Tyr-Tic-NH2, a dipeptide of moderate delta opioid affinity and lacking bioactivity, and with H-Tyr-Tic-Phe-Phe-OH (TIPP), a selective and potent delta opioid receptor antagonist. Clusters I and II superimposed best with three different overlays of naltrindole, a potent delta opiate antagonist, and with two other H-Tyr-Tic-NH delta opioid antagonist pharmacophores proposed by Temussi et al. (1994) and Wilkes and Schiller (1995). The 3-dimensional topography of these two clusters of c(Dmt-Tic) conformations may represent bioactive models for interaction of an antagonist at delta opioid receptors. Cluster I conformers exhibited gauche- (- 64 degrees) and gauche+ (53 degrees) orientations of the side chains Dmt and Tic, respectively, while cluster II contained trans (179 degrees) and gauche+ (62 degrees) orientations of those side-chains. Aromatic ring distances were 5.4 A for cluster I conformations and 8.2 A for cluster II structures. Orientation about the peptide bond N-C' was cis (- 5 degrees and 3 degrees) for both clusters, respectively. These structural features may provide optimal alignment of the physicochemical moieties important for delta opioid receptor interaction, such as the hydrophobic methyl groups of Dmt, hydrogen bonding of the dimethyltyrosine hydroxyl group within the receptor pocket and cation-pi interactions involving the aromatic rings of Dmt and Tic, as profiled by the three point attachment hypothesis.

Topics: Diketopiperazines; Molecular Conformation; Monte Carlo Method; Naltrexone; Narcotic Antagonists; Narcotics; Oligopeptides; Piperazines; Receptors, Opioid, delta; Structure-Activity Relationship; Tetrahydroisoquinolines

We examined the effects of i.c.v. treatment with naltrindole, and the two highly selective peptide delta-opioid receptor antagonists H-Tyr-Tic-Phe-Phe-OH (TIPP) and H-Tyr-Tic psi [CH2-NH]-Phe-Phe- OH (TIPP[psi]), on the development of morphine tolerance and dependence. Each treatment significantly decreased naloxone-precipitated withdrawal, with TIPP[psi] reducing the most symptoms. TIPP[psi], but neither naltrindole nor TIPP, attenuated the development of analgesic tolerance in the tail-flick test. These results suggest that delta-opioid receptors are critically involved in the development of morphine tolerance and dependence.

Topics: Animals; Behavior, Animal; Morphine Dependence; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Rats; Receptors, Opioid, delta; Substance Withdrawal Syndrome; Tetrahydroisoquinolines

Pseudopeptide analogues of the delta opioid antagonists H-Tyr-Tic-Phe-Phe-OH (TIPP) and H-Tyr-Tic-Phe-OH (TIP) containing a reduced peptide bond between the Tic2 and Phe3 residues were synthesized. The two compounds, H-Tyr-Tic psi [CH2NH]Phe-Phe-OH (TIPP [psi]) and H-Tyr-Tic psi-[CH2NH]Phe-OH (TIP [psi]), were tested in mu-, delta-, and kappa-receptor-selective binding assays and in the guinea pig ileum (GPI) and mouse vas deferens (MVD) bioassays. In comparison with their respective parent peptides, both pseudopeptide analogues showed increased delta antagonist potency in the MVD assay, higher delta receptor affinity and further improved delta receptor selectivity. The more potent compound, TIPP [psi], displayed subnanomolar delta receptor affinity and in direct comparisons with other selective delta ligands was shown to have unprecedented delta specificity (Ki mu/Ki delta = 10,500). Furthermore, this compound turned out to be highly stable against enzymatic degradation and, unlike other delta antagonists, showed no mu or kappa antagonist properties. TIPP [psi] is likely to find wide use as a pharmacological tool in opioid research.

Topics: Animals; Binding Sites; Guinea Pigs; Male; Mice; Molecular Conformation; Oligopeptides; Receptors, Opioid, delta; Tetrahydroisoquinolines