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)

The presence and concentrations of each of the three subtypes of opioid receptors (mu, kappa, and delta) has been studied in the accessory optic nuclei (dorsal, lateral, and medial terminal nuclei and the interstitial nucleus of the superior fasciculus, posterior fibers: DTN, LTN, MTN, and inSFp) in normal young rats with radioligands directed towards each opioid receptor subtype. The changes in mu opioid receptors have also been investigated in monocularly enucleated rats in which one eye was removed and the rats sacrificed at postoperative day (PO) 2, 3, 5, 7, 14, and 30. As the MTN is the only accessory optic nucleus of the rat large enough for semiquantitative evaluation, the mu receptor population of the MTN has been subjected to optical microdensitometric analysis. All four of the accessory optic nuclei (AOS nuclei) are found to contain exceedingly high levels of mu opioid receptor binding with the selective radioligand [3H]-[D-Ala,MePhe4, Gly-ol5] (DAGO), low levels of kappa opioid receptor binding using the radioligand [3H]-[ethylketocyclazocine] (EKC) together with the competing agents [D-Pro4]-morphiceptin and [D-Ser2,Thr6]-Leu-enkephalin, and an absence of delta opioid receptor binding with the radioligand [3H]-[D-Ala2,D-Leu5]-enkephalin (DADLE) combined with the competing agent [D-Pro4]-morphiceptin. Monocular enucleation, as studied on the mu opioid receptor population with this experimental approach, results in virtually a complete loss of mu opioid receptors throughout all four of the contralaterally located AOS nuclei, including both dorsal and ventral subdivisions of the medial terminal nucleus (MTNd,v). Kappa and delta receptors are very few (kappa receptors) or are lacking (delta receptors) in the AOS nuclei, and for this reason, the effects of monocular enucleation on these two opioid receptor subtypes have not been investigated. Monocular enucleation also produces a significant lowering in mu receptor binding in other primary optic nuclei (the lateral geniculate nuclei, nucleus of the optic tract, and superficial layers of the superior colliculus) and in the pars principalis of the medial geniculate nucleus (description of changes in mu receptors in non-accessory optic primary optic nuclei will be considered elsewhere). Microdensitometric study of the MTNd,v shows that the decreased binding of mu receptors in this nucleus is barely detectable (about 6%) at PO2 and rises to 6-15% at PO3. At PO5 receptor loss reaches approximately 62%, whereas at PO7 it is about 81% complete. At PO14 and PO30, the mu receptor loss is nearly complete at around 93%.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Opioid receptors in the accessory optic system of the rat: effects of monocular enucleation. 196 79

The affinity of morphine, normorphine, methadone, Tyr-D-Ala-Gly-MePhe-NH(CH2)2(N-O)(CH3)2 (RX 783030), [D-Ala2,D-Leu5]enkephalin (DADLE), ketazocine and ethylketocyclazocine (EKC) were determined for their pharmacological receptors in two bioassay tissues, the guinea-pig ileum and the mouse vas deferens (MVD). The method involved the use of the irreversible antagonist, beta-chlornaltrexamine (beta-CNA), and the method of partial receptor blockade. The agonist concentration-effect curves were displaced to the right with decreasing maximum effect, a pattern typical of partial, irreversible blockade of receptors. The concentrations of beta-CNA required to produce a rightward displacement in the concentration-effect curves for different agonists, ranged between 2 and 3000 nM. No similarity was found between the IC50 and the dissociation constant (KA), values predicted to be equivalent only if a linear relationship exists between receptor occupation and observed effect; the dissociation constant for the agonists were between 3 and 218 times larger than the IC50 values. When methadone was used as the agonist in the guinea-pig ileum, beta-CNA produced parallel displacement of the concentration-effect curve, regardless of the blocking concentration chosen, preventing the determination of KA for this agonist, in this tissue; this problem was not encountered in the mouse vas deferens. The KA of morphine, RX 783030 and ketazocine were found not to differ in the guinea-pig ileum and mouse vas deferens. As expected, DADLE had significantly different affinity in the two tissues, showing 117-fold lower affinity in the guinea-pig ileum. Surprisingly, the normorphine affinity was found to be 7-fold higher in the guinea-pig ileum. While the difference in affinity of DADLE may be due to the suggested lack of functional delta receptors in the guinea-pig ileum, the difference in affinity seen with normorphine, but not morphine, in the two tissues is difficult to explain. Taken together with the insensitivity of methadone to beta-CNA blockade in the guinea-pig ileum, but not mouse vas deferens, the difference in the affinity of normorphine in these tissues may suggest the possibility of differences in local milieu of mu receptors or of mu receptor subtypes in the two tissues. The results provide fundamental information regarding opioid agonist affinity in two standard bioassays in vitro, and support the view of (1) a difference in receptors activated by DADLE in the guinea-pig ileum (mu) and mouse vas deferens (delta), as well as (2) possible differences in mu-receptors in these tissues.
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PMID:Opioid agonist affinity in the guinea-pig ileum and mouse vas deferens. 216 49

Some 2-substituted-(2'-aminophenyl)-4-thioxohydantoic acids (o-amino PTC-amino acids) have antinociceptive activity when administered (icv) alone (IC50 = 0.04-0.87 microM/animal) and show a striking prolongation of the antinociceptive action of (D-Ala-2 D-Leu5)-enkephalin (DADL) in combination. The effects are thought to be mediated via opioid receptors since they are naloxone-reversible. Although inhibitors of the enkephalin degrading puromycin-insensitive, bestatin-sensitive aminopeptidase (possibly aminopeptidase M) their action is weak (IC50 = 32 microM leucine, 536 microM, glycine) and they might be considered to have a direct antinociceptive effect on opioid receptors. The titled compounds constitute novel 'lead' compounds for the development of potent aminopeptidase M inhibitors.
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PMID:Novel inhibitors of enkephalin-degrading enzymes. II: N5'-substituted-4-thioxohydantoic acids as aminopeptidase inhibitors. 248 33

The potencies of several opioid agonists are reduced in diabetic animals and in animals made hyperglycemic via injections of glucose. In this report we examined the effects of streptozotocin-induced diabetes on the feeding responses to centrally administered opioid agonists with differing receptor selectivities. The selective mu receptor agonist Tyr-D-Ala-Gly-(Me)Phe-Gly-ol (DAGO) caused a larger increase in intake in diabetic rats than in controls. In both groups feeding responses were greater on the fourth day of daily injections than on the first day. The delta receptor agonist [D-Ser2,Leu5]-enkephalin-Thr6 (DSLET) stimulated intake in controls but not in diabetics. However, the elevated baseline and large variability in intake of the diabetics in this experiment prevent drawing a conclusion on diabetes-induced changes in the potency of this peptide. No differences between controls and diabetics were apparent in the feeding responses to U50, 488H, a selective kappa receptor agonist. These data suggest that diabetes may differentially affect the classes of opioid receptors or the binding of ligands to these receptors.
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PMID:Effects of streptozotocin-induced diabetes on feeding stimulated by centrally administered opioid agonists. 254 90

The opioid receptor preference for dermorphin and several dimerized structural analogues was investigated using rat brain synaptosomes and correlated with the potencies of intracerebroventricularly administered dimeric dermorphin peptides to inhibit gastric acid secretion. The carboxyl terminus of dermorphin or amino-terminal dermorphin analogues was bridged by dihydrazide or (poly)ethylenediamine structures. Synaptosomal membranes were prepared for radioligand binding assay in the presence of soybean trypsin inhibitor and preincubated to remove endogenously bound opioid peptides before storage at -70 degrees C. Specific radiolabeled agonists used in the radioligand binding assays were [D-Ala2,N-methyl-Phe4,Gly-ol5] [3H] enkephalin for mu-receptors and [D-Ala2,D-Leu5] [3H]enkephalin for delta-receptors. delta-Receptor binding assays were conducted in the presence of 2.6 microM [N-Me-Phe3,D-Pro4]morphiceptin to suppress peptide binding to mu-receptors. [D-Ala2,N-methyl-Phe4,Gly-ol5]enkephalin and dermorphin had affinities of 1.39 and 1.22 nM for mu-receptors and 355.8 and 178.6 nM for delta-receptors, respectively. Affinities of dimeric-dermorphin0 for mu- and delta-receptors, and the mu-selectivity ratio, exceeded values characteristic of dermorphin. The dimerized amino-terminal dermorphin analogues are peptides whose receptor binding differed from the parent molecule; e.g. the affinity of dimeric tetrapeptides toward mu-receptors was reduced but was increased for delta-receptors relative to monomeric dermorphin-(1-4)-amide. Dimeric tetradermorphin linked by a bridge containing 12 methylene units (di-tetra-dermorphin12), exhibited a dramatic loss in the mu-selectivity ratio as a result of diminished mu-affinity. On the other hand, substitution of Gly4 by Sar in di-tetra-dermorphin2 enhanced binding to mu-receptors: substitution of D-Arg2 for D-Ala resulted in an increased binding to mu-receptors while decreasing binding to delta-receptors, yielding a peptide with the highest mu-selectivity ratio. These substitutions of D-Arg2 and Sar4 in dimeric amino-terminal dermorphin pentapeptides enhanced binding to both mu- and delta-receptors relative to dermorphin-(1-5)-amide, but led to a decrease in its mu-selectivity ratio. Several dimeric dermorphin analogues exhibited an enhanced mu-selectivity ratio relative to their monomeric analogues. Dimeric peptides, which had a relatively high affinity for mu-receptors, were effective in the suppression of gastric acid secretion.
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PMID:Dimeric dermorphin analogues as mu-receptor probes on rat brain membranes. Correlation between central mu-receptor potency and suppression of gastric acid secretion. 256 39

The benzophenone chromophore has been incorporated into a synthetic amino acid (p-benzoyl-L-phenylalanine; L-Bpa) to produce a chemically stable photoaffinity probe. L-Bpa was found to retain the photochemical reactivity of benzophenone. To test the utility of this synthetic amino acid as a photo-reactive probe for receptors, a tetrapeptide analog of morphiceptin was made as a model peptide in which the C-terminal prolinamide was replaced by L-Bpa amide. The affinity of the mu opioid receptor for this peptide is comparable to that for the parent compound, morphiceptin. Irradiation of the peptide-receptor complex reduced the subsequent binding of [3H]naloxone and virtually eliminated that of [3H]Tyr-D-Ala-Gly-NMe-Phe-Gly-ol (DAGO). Binding studies with [3H]naloxone indicated that both the affinity and the capacity were reduced. Competition studies with [3H]D-Ala2-D-Leu5-enkephalin (DADLE) and naloxone indicated selective inactivation of a mu type opioid receptor.
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PMID:Photoinactivation of the mu opioid receptor using a novel synthetic morphiceptin analog. 282 33

The tail-flick assay in chronic implanted rats was used to test the analgesic potency of agonists selective for mu opioid receptors: [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAGO), Tyr-D-Ala-Gly-NH(CH2)2-CH(CH3)2 (TRIMU 5) and for delta receptor subtypes: [D-Ser2,Leu5]enkephalyl-Thr6 (DSLET), [D-Thr2,Leu5]enkephalyl-Thr6 (DTLET) and cyclic [D-Pen2,L-Pen5]enkephalin (DPLPE). DAGO produced an analgesic response at a concentration 500 times lower than DPLPE. The relative activity of these compounds was significantly correlated with their affinity for central or peripheral mu receptors but not with their delta receptor affinity. Diffusion studies of tritiated mu and delta agonists showed that after i.c.v. injection, these enkephalin analogues remained essentially localized within supraspinal structures. Taken together these results suggest strongly that the analgesia produced at the supraspinal level by opioid peptides is related to mu receptor stimulation.
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PMID:Use of mu and delta opioid peptides of various selectivity gives further evidence of specific involvement of mu opioid receptors in supraspinal analgesia (tail-flick test). 282 13

The intake of food by rats was measured after unilateral injections of opioid peptides into or near the central nucleus of the amygdala. The selective mu receptor agonist Tyr-D-Ala-Gly-(Me)Phe-Gly-ol (DAGO) caused an increase in intake of food at doses of 1 and 3 nmol. Injections into the amygdala of [D-Ser2,Leu5]enkephalin-Thr6 (DSLET), a selective delta agonist, and dynorphin A, a selective kappa agonist, were ineffective at doses up to 3 nmol. However, dynorphin (2 nmol) did increase intake when injected into the medial hypothalamus. Bilateral injections of DAGO into the amygdala were no more effective than unilateral injections. The effect of DAGO was blocked by injections into the amygdala of naloxone or beta-chlornaltrexamine, an ultralong-lasting opioid receptor antagonist. These studies suggest that mu opioid receptors in the amygdala contribute to the regulation of intake of food. A role for kappa and delta receptors was not established but cannot be ruled out without further testing.
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PMID:Involvement of mu opioid receptors in the amygdala in the control of feeding. 283 55

In order to clarify the effects of endogenous opiate peptides on the vasopressin system, we have investigated the presence of different opiate receptor subtypes in the neurohypophysis by radioreceptor assay and autoradiography. [3H]-etorphine binding to membrane preparations revealed the presence of high- and low-affinity binding sites (KD, 1.2 nM and 8.1 nM). Displacement of [3H]-etorphine by opiate receptor subtype-specific ligands gave the following results: the preferential mu agonists DAGO (Tyr-D-Ala-Gly-NMe-Phe-Gly-oL) and the tetrapeptide morphiceptin did not displace etorphine; the preferential sigma receptor agonists DADLE (D-Ala2,D-Leu5-enkephalin) or DSTLE (D-Ser2,Leu5,Thr6-enkephalin) and beta-endorphin, a preferential agonist of the epsilon receptor, displaced [3H]-etorphine from its low-affinity site only, and dynorphin 1-8, a preferential kappa agonist, displaced [3H]-etorphine from its high-affinity binding site. Film autoradiography of neurohypophyseal sections incubated with [3H]-etorphine showed a displacement of 30% of the labeled ligand by unlabeled dynorphin 1-8. Exposure of rat neurointermediate lobes in organ culture to dynorphin 1-8 caused a small but significant stimulation of vasopressin release. These results demonstrate the existence of dynorphin 1-8 sensitive opiate receptors of the kappa subtype in the neurohypophysis and their possible involvement in vasopressin release.
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PMID:Dynorphin 1-8 binds to opiate kappa receptors in the neurohypophysis. 287 1

beta-Chlornaltrexamine (beta-CNA) is a non-equilibrium opioid receptor antagonist which alkylates and inactivates opioid receptors. Because opioid peptides are thought to contribute to the regulation of food intake, we examined the effects of intracerebroventricular (icv) injections of beta-CNA on the food intake and body weight of male rats. We also tested the ability of beta-CNA to block food intake stimulated by selective agonists of kappa, mu and delta opioid receptors: dynorphin A2 (DYN), Tyr-D-Ala-Gly-(Me)Phe-Gly-ol (DAGO), and [(D-Ser2,Leu5]-enkephalin-Thr6 (DSLET). Treatment with beta-CNA caused a long-term (2-4 days) reduction in daily food intake and a concomitant reduction in body weight. An additional experiment indicated that the weight loss after beta-CNA treatment could be completely accounted for by the reduction in intake. beta-CNA treatment also abolished or greatly attenuated the feeding effects of DAGO, DSLET and DYN, even when these peptides were tested 26 hours after beta-CNA administration. The long duration of the effects of beta-CNA suggests that this compound will be a useful pharmacological tool in further study of the opioid feeding system.
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PMID:Effects of beta-chlornaltrexamine on food intake, body weight and opioid-induced feeding. 288 1


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