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)

A bioactive, fluorescent derivative of enkephalin, Tyr-D-Ala-Gly-Phe-Leu-Lys-rhodamine, was used to determine the distribution of opiate receptors in living neuroblastoma cells. The receptors appeared in clusters on the cell surface, and no internalization was detected. No specific fluorescence or clusters were observed in the presence of [D-Ala2, Leu5]enkephalin or at 4 degrees C, and the clusters were much reduced under ionic conditions (that is, with 100 millimolars sodium) that specifically decrease the binding of opiate agonists.
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PMID:Opiate (Enkephalin) receptors of neuroblastoma cells: occurrence in clusters on the cell surface. 22 58

A series of individual D-amino acid replacement analogues of deltorphin A, several of which were in combination with a His4 deletion, were used to probe alterations of side-chain orientation on peptide binding parameters with rat brain opioid receptors. Peptides with D-amino acids in residues 1, 3, and 5 exhibited diminished affinities primarily for delta receptors (88-1200-fold) with selectivity decreasing by factors of 13-64-fold relative to deltorphin A (Ki delta = 0.45 nM; Ki mu/Ki delta = 764): the aromatic side chains Tyr1 and Phe3, which lie in the N-terminal "message" domain and the aryl side chain of Leu5 in the C-terminal "address" domain, appear to play essential roles in conferring high delta affinity and selectivity. Although D-His4 only decreased delta affinity by 6-fold and selectivity by a factor of 4, His appears to be involved as an integral component of both domains: [des-His4]deltorphin A and [des-His4] analogues containing consecutive D-amino acid replacements in the remaining residues exhibited weak binding to delta receptors and poor delta selectivity. Substitution of D-Met2 in deltorphin A by D-Ala or D-Nle decreased delta selectivities 3-6-fold through an elevation in mu affinities; however, the converse replacement, D-Met for D-Ala2 in deltorphin B, diminished beta selectivity by an order of magnitude only through the loss in delta affinity. The data show that the high delta affinity and selectivity of deltorphins correlate with and require a strict stereospecificity of the amino acid residue side chains.
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PMID:Stereospecificity of amino acid side chains in deltorphin defines binding to opioid receptors. 131 78

Recent pharmacological data strongly support the hypothesis of delta receptor subtypes as mediators of both supraspinal and spinal antinociception (delta 1 and delta 2 receptors). In vitro ligand binding data, which are fully supportive of the in vivo data, are still lacking. A previous study indicated that [3H][D-Ala2,D-Leu5]enkephalin labels two binding sites in membranes depleted of mu binding sites by pretreatment with the site-directed acylating agent, 2-(p-ethoxybenzyl)-1-diethylaminoethyl-5-isothiocyanatobenzimid azole-HCI (BIT). The main goal of the present study was to develop a ligand-selectivity profile of the two delta ncx binding sites. The data indicated that naltrindole and oxymorphindole were relatively selective for site 1 (20-fold). [D-Ser2,Thr6]Enkephalin and deltorphin-II were only 2.7-fold and 2.2-fold selective for site 1. [D-Pen2,D-Pen5]Enkephalin and deltorphin-I were 80-fold and 38-fold selective for site 2. 3-Iodo-Tyr-D-Ala-Gly-Phe-D-Leu was 52-fold selective for site 1. Morphine had moderate affinity for site 1 (Ki = 16 nM), and was about 11-fold selective for site 1. Thus, of the 10 drugs studied, only DPDPE and DELT-I were selective for site 2. Viewed collectively with other data, it is likely that the delta 1 receptor and the delta ncx binding site are synonymous.
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PMID:Interaction of opioid peptides and other drugs with multiple delta ncx binding sites in rat brain: further evidence for heterogeneity. 133 80

Tolerance in the longitudinal muscle-myenteric plexus (LM-MP) preparation to opioids appears to represent two separate phenomena. One phenomenon is characterized by marked subsensitivity to mu-selective opioid substances and a very short half-life. The other is characterized by moderate subsensitivity to morphine and to several nonopioid inhibitory substances and has a long half-life. The present investigation was to determine if the long half-life type of tolerance involves cross-tolerance between mu-selective opioids, such as morphine, and opioids selective for delta or kappa receptors. Tolerance was induced by s.c. implantation of morphine pellets for 7 days. Control guinea pigs received placebo pellets. Isolated LM-MP preparations were tolerant to the mu-selective agonists morphine and [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin as well as to [D-Ala,2D-Leu5]enkephalin and [D-Ser2]leucine enkephalin-Thr, agonists only slightly selective for delta receptors over mu. The delta-selective agonist, [D-Pen2,D-Pen3]enkephalin, produced a biphasic concentration-response curve. The first phase, which included only very weak effects, presumably represented delta-mediated effects. The second phase reached virtually 100% inhibition of the twitch. Significant subsensitivity (tolerance) was demonstrated only for the second phase, presumably representing mu-mediated effects. There was no significant tolerance to the kappa-selective agonist, U50,488H. Consistent with the literature, the results indicate effective twitch inhibition mediated by mu and kappa receptors, but not delta receptors. Among opioids, tolerance induced by morphine pellets in the LM-MP is limited to mu receptor-mediated inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Involvement of mu, delta and kappa receptors in morphine-induced tolerance in the guinea pig myenteric plexus. 165 24

1. To elucidate the structural features required for selective and potent action of dermenkephalin at the delta-opioid receptor, a series of analogues of dermenkephalin and dermorphin were tested for their effectiveness in depressing electrically-evoked contractions of the vas deferens of the hamster (delta-opioid receptors) and the guinea-pig myenteric plexus-longitudinal muscle preparation (mu- and kappa-opioid receptors). 2. Dermenkephalin was more selective and more potent at delta-receptors than the delta-ligand [D-Pen2, D-Pen5]-enkephalin. The responses to dermenkephalin in the hamster vas deferens were increased by addition of peptidase inhibitors; the maximum effect was obtained with 3 microM thiorphan. 3. [L-Met2]-dermenkephalin had 0.2% and [L-Ala2]-dermorphin 0.01% of the agonist activity of the corresponding endogenous peptides which have D-amino acids in position 2. The pharmacological activity of these analogues was unaffected by inhibition of peptidases. This emphasizes the role that the D-configuration plays in determining the bioactive folding of these highly active peptides. 4. Dermenkephalin-(1-6)-NH2 was more potent at delta-receptors than at mu-receptors whereas, dermenkephalin-(1-4)-NH2 is a selective mu-agonist, having no activity at delta-receptors. 5. Substitution of the C-terminal tripeptide of dermorphin with the C-terminal tripeptide of dermenkephalin abolished the mu-receptor preference of dermorphin. The resulting hybrid peptide, Tyr-D-Ala-Phe-Gly-Leu-Met-Asp-NH2 was as potent as dermenkephalin at delta-receptors. A shift towards a preference for delta-receptors was obtained when the C-terminal tetrapeptide of dermorphin was replaced by the C-terminal tetrapeptide of dermenkephalin. 6. Substitution of Asp by Asn in position 7 of dermenkephalin caused an increase in mu-receptor potency and a decrease in delta-receptor potency, resulting in a 20 fold decrease in mu-receptor selectivity. Dermenkephalin-(1-6)-NH2 and [Asn7]-dermenkephalin have almost identical delta-receptor agonist potencies and ratios of IC50 in the myenteric plexus to IC50 in the hamster vas deferens. 7. The results obtained emphasise the importance of a negative charge at the C-terminus of dermenkephalin for selectivity at the delta-opioid receptor. Furthermore, the hydrophobic residues Leu5 and Met6 may be critical in ensuring tight binding to the receptor which results in high agonist potency.
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PMID:Opioid activity of dermenkephalin analogues in the guinea-pig myenteric plexus and the hamster vas deferens. 166 35

1. The potency, relative efficacy and selectivity of a series of kappa-opioid receptor agonists at the mu-, delta- and kappa-opioid receptors mediating inhibition of electrically-induced (radiolabelled) neurotransmitter release from superfused rat brain slices was determined. 2. With regard to their potencies at kappa-receptors mediating inhibition of striatal [3H]-dopamine release, the highest pD2 value (8.7) was found for bremazocine and the lowest (7.1) for U50488; the pD2 values for ethylketocyclazocine (EKC), tifluadom, U69593 and PD117302 were between 8.0 and 8.3. There were no marked differences between the relative efficacies of the kappa-agonists (maximum inhibition being 60-70%). In contrast to the other kappa-agonists, at a concentration of 1 microM, PD117302 caused a significant (25-40%) increase of the spontaneous efflux of tritium. 3. None of the kappa-agonists significantly affected striatal [14C]-acetylcholine (ACh) release, with the exception of a slight inhibitory effect of EKC. The delta-receptor-mediated inhibitory effect of [D-Ala2, D-Leu5]enkephalin (DADLE) on [14C]-ACh release was antagonized in a concentration-dependent manner by bremazocine (0.1 and 1.0 microM) and also partially by EKC (1 microM), but not by the other kappa-agonists. The pA2 value for bremazocine as an antagonist at the delta-receptors involved was 8.0, compared to 7.6 for naloxone. 4. None of the kappa-agonists significantly affected cortical [3H]-noradrenaline (NA) release, with the notable exception of tifluadom, which strongly inhibited release by activating mu-receptors. The mu-receptor-mediated inhibitory effect of Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAMGO) on [3H]-NA release was antagonized in a concentration-dependent manner by bremazocine and EKC, but not by the other K-agonists. The pA2 value for bremazocine as an antagonist at the mu-receptors involved was 8.2, compared to 8.6 for naloxone. 5. Thus, whereas U69593 and PD1 17302 display high potency and selectivity towards K-opioid receptors, the potent benzomorphan K-agonists bremazocine and EKC also appear to be strong mu-opioid receptor antagonists.
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PMID:Pharmacological profile of various kappa-agonists at kappa-, mu- and delta-opioid receptors mediating presynaptic inhibition of neurotransmitter release in the rat brain. 167 74

The opioid receptor antagonist properties of four conformationally constrained cyclic octapeptide analogues of somatostatin were investigated using in vitro functional paradigms of mu-, delta- and kappa-opioid receptors in the rat brain. The analogues examined were D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), D-Tic-CTOP (TCTOP) and D-Tic-CTAP (TCTAP). Activation of mu-receptors by the enkephalin analogue Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAGO) inhibited the (electrically evoked) release of [3H]noradrenaline (NA) from superfused cortical slices and this inhibitory effect was antagonized in a competitive fashion by all of the octapeptides tested (pA2 values: CTOP and CTAP 7.9-8.0, TCTOP and TCTAP 8.7-8.8). Selective activation of kappa-opioid receptors by the cyclohexylbenzeneaceamide U69593 (0.02 microM) inhibited (by 40-45%) the release of [3H]dopamine (DA) from striatal slices, whereas selective activation of delta-opioid receptors by [D-Ser2(O-t-butyl),Leu5]enkephalyl-Thr6 (DSTBULET; 0.1 microM) caused an inhibition (by 38-46%) of striatal [14C]acetylcholine (ACh) release. However, these inhibitory effects were not affected by any of the octapeptides in concentrations that caused full antagonism of the inhibitory effect (55-65%) of 0.1 microM DAGO on cortical [3H]NA release. Thus, the cyclic octapeptide somatostatin analogues CTOP, CTAP, TCTOP and TCTAP are potent and highly selective antagonists at the mu-opioid receptors mediating presynaptic inhibition of NA release in the brain. The mu-receptor affinity of the most potent of these antagonists, TCTOP and TCTAP, appears to be similar to that of naloxone but these antagonists have a much greater selectivity than the latter.
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PMID:Cyclic somatostatin analogues as potent antagonists at mu-, but not delta- and kappa-opioid receptors mediating presynaptic inhibition of neurotransmitter release in the brain. 168 63

The opioid modulation of histamine release was studied in rat brain slices labeled with L-[3H]histidine. The K(+)-induced [3H]histamine release from cortical slices was progressively inhibited by the preferential kappa-agonists ketocyclazocine, dynorphin A (1-13), Cambridge 20, spiradoline, U50,488H, and U69,593 in increasing concentrations. In contrast, the mu-agonists morphine, morphiceptin, and Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAGO) were ineffective as were the preferential delta-agonists [D-Ala2,D-Leu5]enkephalin (DA-DLE) and [D-Pen2,D-Pen5]enkephalin (DPDPE). Nor-binaltorphimine (nor-BNI) and MR 2266, two preferential kappa-antagonists, reversed the inhibitory effect of the various kappa-agonists more potently than did naloxone, with mean Ki values of 4 nM and 25 nM, respectively. The effects of ketocyclazocine and naloxone also were seen in slices of rat striatum, another brain region known to contain histaminergic nerve endings. We conclude that kappa-opioid receptors, presumably located on histaminergic axons, control histamine release in the brain. However, nor-BNI and naloxone failed, when added alone, to enhance significantly [3H]histamine release from cerebral cortex or striatum, and bestatin, an aminopeptidase inhibitor, failed to decrease K(+)-evoked [3H]histamine release. These two findings suggest that under basal conditions these kappa-opioid receptors are not tonically activated by endogenous dynorphin peptides. The inhibition of cerebral histamine release by kappa-agonists may mediate the sedative actions of these agents in vivo.
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PMID:Modulation of histamine release in the rat brain by kappa-opioid receptors. 169 48

Chronic treatment of neuroblastoma x glioma NG108-15 hybrid cells with the opioid agonist D-Ala,2 D-Leu5-enkephalin (DADLE) induces a homologous desensitization of the delta opioid receptors present in these cells. Since the Kd value of the delta opioid receptor's high-affinity state reflects the potency of the agonist, we examined the effect of receptor desensitization in NG108-15 cells on the percentage of receptor in the high-affinity state. When NG108-15 hybrid cells were treated with 10 or 100 nM DADLE for 4 hr at 24 degrees C, loss of DADLE's ability to inhibit adenylate cyclase was observed. However, when competition binding experiments were carried out with P2P3 membranes isolated from the delta opioid-desensitized hybrid cells, it was determined that 41.7 +/- 3.4% of the total binding sites remained in the high-affinity state, with no apparent alteration in the Kd value of either high- or low-affinity states. Similarly, when NG108-15 cells were treated with 100 ng/ml of pertussis toxin for 3 hr at 37 degrees C, 39.9 +/- 3.6% of the binding sites remained in the high-affinity state. This reduction in the percentage of receptor in high-affinity state was agonist specific, for chronic treatment of hybrid cells with levorphanol, a partial agonist, or the antagonist naloxone did not alter the percentage of opioid receptors in the high-affinity state. Furthermore, the delta opioid receptors remaining in the high-affinity state after chronic DADLE treatment were still sensitive to both Na+ and guanyldylimidodiphosphate, indicating that opioid ligand binding remained coupled to the G-proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of chronic D-Ala,2 D-Leu5-enkephalin or pertussis toxin treatment on the high-affinity state of delta opioid receptor in neuroblastoma x glioma NG108-15 hybrid cells. 184 9

Several peptides of diverse structure, reported to possess high affinity and selectivity for the delta opioid receptor, were studied using the mouse isolated vas deferens preparation to determine the effect of peptidase inhibition on their apparent potency. The peptides evaluated included [Leu5] enkephalin, the cyclic enkephalin analogs [D-Pen2,D-Pen5]enkephalin (DPDPE) and [D-Pen2,p-F-Phe4,D-Pen5]enkephalin (F-DPDPE), the linear enkephalin analogs [D-Ala2,D-Leu5]enkephalin (DADLE) and [D-Ser2(O-tBu), Leu5,Thr6]enkephalin (DSTBULET), and the naturally occurring amphibian peptides Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2 (dermenkephalin), Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2 (deltorphin I) and Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2 (deltorphin II). Concentration-response curves were determined for each peptide in the absence and presence of a combination of the peptidase-inhibiting agents bacitracin, bestatin, and captopril. A wide range of potencies was observed, both in the control state and in the presence of peptidase inhibition. The synthetic enkephalin analogs demonstrated small increases in potency with peptidase inhibition (no increase in the case of DPDPE), whereas the naturally occurring peptides were markedly increased in potency, up to as much as 123-fold for dermenkephalin. In the presence of peptidase inhibition, deltorphin II was the most potent peptide tested (IC50 = 1.13 x 10(-10) molar), and as such is the most potent delta opioid agonist reported to date. Stability to metabolism must be considered in the design and evaluation of in vitro experiments using peptides of this type.
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PMID:Influence of peptidase inhibitors on the apparent agonist potency of delta selective opioid peptides in vitro. 184 36


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