Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:338-69-2 (D-Ala)
 1,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two series of dimeric enkephalin analogues were assayed for opioid activity in two isolated smooth muscle preparations: the guinea pig ileum (GPI) and the mouse vas deferens (MVD). Dimers have the general structure: X-(CH2)n-X, where X is H-Tyr-D-Ala-Gly-Phe-Leu-NH-(n = 0, 2, 4, 6, 8, 10, 12), for the first series of dimeric pentapeptide enkephalins (DPEn), and H-Tyr-D-Ala-Gly-Phe-NH-(n = 2, 4, 6, 8, 12), for the series of dimeric tetrapeptide enkephalins (DTEn). Comparison of biological activities with binding affinities revealed that: (1) the DPE series with n = 2-8 showed increased potency in the MVD assay relative to monomeric [D-Ala2, Leu5]enkephalinamide (DALEA); (2) there was an associated increase affinity for the delta receptor of rat brain or neuroblastoma-glioma hybrid cells. (however, the relative potencies were higher in the MVD assay then predicted on the basis of binding affinities); (3) the DTE series also showed an increase in delta receptor affinities and MVD potencies relative to DALEA, for n = 2-12; (4) for the DTE series, the increase in MVD activities was less than that expected on the basis of delta binding affinity; (5) for both the DPE and DTE series, activities in the GPI assay and mu-receptor affinities were highly correlated: as the length of the methylene bridge increased from 2 to 12, there was a progressive loss of activity in both assays, with a similar pattern for DPE and DTE. Two selected dimers and their corresponding monomers were also assayed for antinociceptive activity in vivo: results were consistent with GPI and mu-binding but not with MVD and delta-binding. Two alkylamide analogs of penta- and tetrapeptide monomers, representing the monomer with the attached spacer of the most active dimers, were also assayed in biological and binding assays. Comparison of these compounds with the corresponding dimers suggest that the changes in activities and selectivities induced by dimerization are not a spurious effect of the presence of an akylamide derivative of the carboxy terminal of enkephalin but rather may represent a specific effect due to the bivalent nature of the ligands.
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PMID:Receptor binding and biological activity of bivalent enkephalins. 298 28

We have identified mu, delta and kappa opioid binding sites in four types of neural membranes under conditions which include physiological concentrations of ions and an incubation temperature of 37 degrees C. We hypothesize that binding parameters determined under these conditions should be more directly comparable with physiological experiments than parameters obtained under conditions of low ionic concentration and at low temperature. By using either a radioligand which is selective for a single type of opioid binding site or a relatively nonselective radioligand in the presence of an unlabeled selective ligand, we have isolated binding to single populations of sites. Saturation and displacement data were analyzed with the aid of a computerized nonlinear curve fitting program. [3H]Tyr-D-Ala-Gly-(Me)Phe-Gly-ol bound to a single population of sites with the characteristics of mu receptors, as determined by saturation and displacement analysis. Binding to the mu site represented 70% of the total specific opioid binding in rat brain, but only 20 to 30% in guinea-pig tissues. [3H][D-Ala2-D-Leu5]enkephalin bound almost equally well to mu and delta sites, but the delta site could be examined by the inclusion of unlabeled Tyr-D-Ala-Gly-(Me)Phe-Gly-ol in the incubations. [3H]Ethylketocyclazocine bound mu and kappa sites, and Tyr-D-Ala-Gly-(Me)Phe-Gly-ol was also used to block the mu component in experiments in which we studied kappa binding. Binding to kappa sites represented 50 to 60% of the total in guinea-pig tissues, but less than 20% in rat brain.
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PMID:Opioid binding to rat and guinea-pig neural membranes in the presence of physiological cations at 37 degrees C. 298 94

Unilateral injections of a putative kappa-opiate receptor agonist, ethylketocyclazocine, into the globus pallidus of rats caused dose-dependent ipsiversive circling which was inhibited by prior systemic administration of the opiate receptor antagonist naloxone. Neither a putative delta-opiate receptor agonist ( [D-Ala2, D-Leu5]enkephalin) nor a putative mu-opiate receptor agonist (Tyr-D-Ala-Gly-MePhe-Met(0)-ol) induced circling behaviour after unilateral intrapallidal injection. Bilateral intrapallidal injection of the delta-opiate receptor agonist or the mu-opiate receptor agonist caused an increase in locomotor activity which in both cases was reduced by systemic administration of naloxone. A specific delta-receptor antagonist, (N,N-bisalyl-Tyr-Gly-Gly-psi-(CH2S)-Phe-Leu-OH) had no effect on the increase in locomotor activity caused by the delta-opiate receptor agonist. Bilateral intrapallidal injection of the kappa-opiate receptor agonist had no effect on locomotor activity. It is suggested that different opiate receptor subtypes within the globus pallidus differentially mediate circling and locomotor behaviour.
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PMID:Behavioural effects in rats of unilateral and bilateral injections of opiate receptor agonists into the globus pallidus. 298 29

The binding of alkylendiamide dimers of the three N-terminal residues of [D-Ala2,D-Leu5]enkephalin (DADL) to rat brain and Ng108-15 neuroblastoma-glioma cell membranes was compared with that of DADL, Tyr-D-Ala-Gly-NMe-Phe-Gly-ol (DAGO) and morphiceptin. Tritiated DADL and DAGO were used as labeled ligands for delta- and mu-receptors, respectively. Dimerization of the tripeptides resulted in dramatic increases in both mu and delta binding. The binding to mu-receptors showed two peaks at an alkyl chain length of n = 2 and approximately n = 16. In contrast, delta binding (NG108-15 cells) increased steadily with increasing chain length. The dimers with n less than 18 were mu-preferential, and the one with n = 2 showed the most dramatic increase in mu selectivity with a 400 fold higher affinity to mu- than to delta-receptors. For long-chain alkyl spacers the compounds became delta selective.
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PMID:Increased affinity and selectivity of enkephalin tripeptide (Tyr-D-Ala-Gly) dimers. 299 Sep 53

In rats the influence of the delta opioid agonists [Leu]enkephalin, [D-Ala2-D-Leu5]enkephalin, [D-Ala2]methionine enkephalinamide and synthetic analogue of [Met]enkephalin: Tyr-D-Ala-Gly-Phe-D-Leu-OMe on audiogenic seizures was tested during ethanol abstinence. All investigated drugs significantly inhibited this ethanol withdrawal symptom. The results are compatible with the hypothesis of opioid involvement in the ethanol abstinence syndrome.
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PMID:Audiogenic seizures during ethanol withdrawal can be blocked by a delta opioid agonist. 302 46

Synaptosomes prepared from rat cerebral cortex and labeled with [3H]noradrenaline (NA) were superfused with calcium-free Krebs-Ringer-bicarbonate medium and exposed to 10 mM K+ plus 0.1 mM Ca2+ so that [3H]NA release was induced. 6,7-Dihydroxy-N,N-dimethyl-2-aminotetralin (TL-99) strongly inhibited synaptosomal K+-induced [3H]NA release (EC50 = 5-10 nM) by activating alpha 2-adrenoceptors. Release was also inhibited (maximally by 40-50%) by morphine (EC50 = 5-10 nM), [Leu5]enkephalin (EC50 = approximately 300 nM), [D-Ala2,D-Leu5]enkephalin (DADLE), and Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAGO) (EC50 values = approximately 30 nM). In contrast to the mu-selective opioid receptor agonists morphine and DAGO, the highly delta-selective agonist [D-Pen2,D-Pen5]enkephalin (1 microM) did not affect [3H]-NA release. Furthermore, the inhibitory effect of DADLE, an agonist with affinity for both delta- and mu-opioid receptors, was antagonized by low concentrations of naloxone. The findings strongly support the view that, like alpha 2-adrenoceptors, mu-opioid receptors mediating inhibition of NA release in the rat cerebral cortex are localized on noradrenergic nerve terminals.
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PMID:Morphine and enkephalins potently inhibit [3H]noradrenaline release from rat brain cortex synaptosomes: further evidence for a presynaptic localization of mu-opioid receptors. 302 24

The C-terminal chloromethyl ketone derivative of D-Ala2-Leu5-enkephalin (DALECK) has previously been shown to act as an affinity reagent at opioid receptors. The specificity of this derivative in its reversible interaction with functional opioid receptors has been examined here in a set of four field-stimulated isolated tissue preparations; the mouse, rat and rabbit vas deferens and the guinea pig ileum. Agonist potencies relative to selective reference agonists and Schild analysis were used to elucidate the overall activity of DALECK when interacting reversibly with opiate receptors under normal physiological conditions in the isolated tissue preparations. Under these conditions the ligand shows a very strong mu-selectivity. Data obtained in the guinea pig ileum suggest that DALECK is more potent than Tyr-D-Ala-Gly-N(CH3)Phe-Gly-ol (DAGO) when acting through mu-receptors. In contrast in the mouse vas deferens DALECK is at least 70-fold less potent than the delta-ligand D-Thr2-Leu5-enkephalin-Thr (DTLET). DALECK shows little interaction with kappa-receptors.
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PMID:Specificity of the opioid affinity reagent, DALECK, in a set of isolated tissue assay systems. 302 19

The potent opiate radioligands [3H]etorphine, [3H]ethylketocyclazocine (EKC), and [3H]naloxone, bound specifically and saturably to a single class of membrane-binding sites in rat neurointermediate lobe (NIL), with Kd values of 3.7, 24, and 51 nM, respectively. In the hypothalamus (Ht), [3H]etorphine bound to specific and saturable sites with a Kd of 2.9 nM. Binding-inhibition studies with [3H]etorphine and unlabeled etorphine-HCl as well as [3H]EKC and unlabeled EKC, revealed high and low affinity binding sites in rat Ht and NIL as well as in the neural lobe of the bovine pituitary gland. [3H]naloxone also bound specifically to two classes of sites in Ht membranes, but to only a single class of low affinity sites in NIL membranes. Specific binding represented 80-90% of total [3H]etorphine binding, about 75% of total [3H]EKC binding, and 45-55% of total [3H]naloxone binding at 22 C in NIL and Ht, respectively. Relative binding potencies derived from Ki values for binding-inhibition studies of [3H]etorphine with opioid peptides and opiates were: NIL, etorphine-HCl greater than dynorphin A greater than naloxone-HCl greater than dynorphin-(1-9) greater than beta-endorphin much greater than alpha-neoendorphin approximately (Leu5)enkephalin approximately DAGO (Tyr-D-Ala-Gly-NMe-Phe-Gly-ol); Ht, etorphine HCl greater than naloxone-HCl greater than beta-endorphin greater than dynorphin A much greater than DAGO greater than morphiceptin much greater than (Leu5)enkephalin. Specific [3H]etorphine binding was also demonstrable after preincubation of NIL membranes with DAGO and (Leu5)enkephalin and after preincubation of Ht membranes with morphiceptin and (Leu5)enkephalin; such binding could be displaced by nonradioactive dynorphin A. In addition, [3H]etorphine binding to bovine neural lobe was displaceable by naloxone-HCl, with an ED50 of 43 nM. Specific ligands for sigma-opiate receptors, such as (+)SKF 10,047 (N-allylnorcyclazocine), phencyclidine (PCP), and (-)cyclazocine, displaced specifically bound [3H]etorphine and [3H]EKC from NIL membranes only at high (micromolar) concentrations. However, specific [3H]PCP sites were of higher affinity in NIL and Ht membranes, with similar Kd values of 102 and 190 nM respectively, and different concentrations (0.15 and 1.32 pmol/mg protein, respectively). These data have revealed several differences in the opiate-binding properties of rat Ht and NIL membranes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Opiate receptor subtypes in the rat hypothalamus and neurointermediate lobe. 303 71

The effects of (D-Ala2,D-Leu5)enkephalinamide, a synthetic analogue of (Leu5) enkephalin, on the contractile activity of isolated segments from guinea-pig and rat colon and rectum were investigated and compared to the effects of natural (Leu5)enkephalin. It was found that the contractile effects of (D-Ala2,D-Leu5)enkephalinamide vary between species and according to the route of administration (application of single doses of cumulative application). (D-Ala2,D-Leu5)enkephalinamide was more potent than (Leu5)enkephalin. It is suggested that in the separate regions of the guinea-pig and rat intestines (D-Ala2,D-Leu5)enkephalinamide activates the same opiate receptors as (Leu5)enkephalin. The higher potency of (D-Ala2,D-Leu5)enkephalinamide could be due to its retarded enzyme degradation because of the replacement of Gly2 by D-Ala and of Leu5 by D-Leu. A selective activation of delta type opiate receptors by (D-Ala2, D-Leu5)enkephalinamide is also assumed.
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PMID:Effects of (D-Ala2,D-Leu5)enkephalinamide on isolated longitudinal muscle guinea pig and rat intestines. 361 57

The food intake of rabbits was measured after intracerebroventricular injections of several opioid agonists and naloxone. The preferential kappa agonist dynorphin A increased intake, while naloxone, [D-Ser2,Leu5]enkephalin-Thr6 and Tyr-D-Ala-Gly-(Me)Phe-Gly-ol reduced intake or had no effect. These results suggest that kappa receptors have a role in the control of feeding in rabbits.
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PMID:Opioid peptide effects on feeding in rabbits. 379 41


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