LY164929: a highly selective ligand for the lower affinity [3H]D-Ala2-D-Leu-5-enkephalin binding site

Rothman, Richard B.; Bykov, Victor; Ofri, Danielle; Rice, Kenner C.

doi:10.1016/0143-4179(88)90022-4

Cited by 31 publications

(26 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The binding affinities of the new analogs of 2n for μ and δ receptors were determined by inhibition of binding of [ 3 H]DAMGO (Tyr- d -Ala-Gly-(Me)-Phe-Gly-ol) and [ 3 H]DADLE (Tyr- d -Ala-Gly-Phe- d -Leu) at rat brain membranes. The affinity of these derivatives for κ receptors was determined by inhibition of binding of [ 3 H]U69,593 at guinea pig brain membranes.…”

Section: Resultsmentioning

confidence: 99%

“…The nonspecific binding was determined using 20 μM levallorphan. δ Binding sites were labeled using [ 3 H]DADLE (1.7−2.5 nM) and rat brain membranes as previously described . Incubations proceeded for 3−4 h at 25 °C in 10 nM Tris-HCl, pH 7.4, containing 100 mM choline chloride, 3 mM MnCl 2 , and 100 nM DAMGO to block binding to μ sites and PIC.…”

Section: Methodsmentioning

confidence: 99%

“…δ Binding sites were labeled using [ 3 H]-DADLE (1.7-2.5 nM) and rat brain membranes as previously described. 32 Incubations proceeded for 3-4 h at 25 °C in 10 nM Tris-HCl, pH 7.4, containing 100 mM choline chloride, 3 mM MnCl2, and 100 nM DAMGO to block binding to µ sites and PIC. Nonspecific binding was determined using 20 µM levallorphan.…”

Section: (-)-2-[(rs)-r-{(2s5r)-4-allyl-25-dimethyl-1-piper-azinyl}ben...mentioning

confidence: 99%

See 2 more Smart Citations

Probes for Narcotic Receptor-Mediated Phenomena. 25. Synthesis and Evaluation ofN-Alkyl-Substituted (α-Piperazinylbenzyl)benzamides as Novel, Highly Selective δ Opioid Receptor Agonists

et al. 1997

Self Cite

View full text Add to dashboard Cite

A series of N-alkyl- and N,N-dialkyl-4-[alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl] benzyl]-benzamides were synthesized and evaluated for binding affinities at mu, delta, and kappa opioid receptor subtypes. Several compounds (2e,f,h,i,m) strongly bound to the delta receptor with IC50 values in the nanomolar range. On the other hand, the binding affinities of these compounds for the mu and kappa receptors were in the micromolar or greater range indicating excellent delta opioid receptor subtype selectivities. In this series, two important structure-activity relationships were found for the delta receptor binding affinity. First, the spatial orientation of the alpha-benzylic position influenced the affinities with the alpha R derivatives 2a-n generally showing more than 10-fold greater affinity than the alpha S derivatives 3a-n. Second, the binding affinities were strongly influenced by the number of alkyl substituents on the amide nitrogen. N-Monoalkylbenzamide derivatives 2b-d showed lower affinity than N,N-dialkylbenzamide derivatives 2e-n, and the N-unsubstituted benzamide derivative 2a had the lowest affinity for the delta receptor in the series. The dramatic effect of the amide group substitution pattern on the binding affinity for the delta receptor strongly suggests that the amide function is an important structural element in the interaction of this series of compounds at the delta receptor. Selective compounds in this series were examined for binding affinity in cloned human mu and delta receptors. The results obtained generally paralleled those from the rat brain binding assay. Compounds 2e,f with potent delta binding affinities and high delta selectivities were shown to be delta agonists with high selectivity by studies in the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. Compound 2f was the most selective compound in the rat brain and GPI/MVD assays with 1755- and 958-fold delta vs mu selectivity, respectively.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: (-)-2-[(rs)-r-{(2s5r)-4-allyl-25-dimethyl-1-piper-azinyl}ben...mentioning

confidence: 99%

See 1 more Smart Citation

Probes for Narcotic Receptor-Mediated Phenomena. 25. Synthesis and Evaluation ofN-Alkyl-Substituted (α-Piperazinylbenzyl)benzamides as Novel, Highly Selective δ Opioid Receptor Agonists

et al. 1997

Self Cite

View full text Add to dashboard Cite

show abstract

“…The nonspecific binding was determined using 20 μM levallorphan. δ binding sites were labeled using [ 3 H]DADLE (1.7−2.5 nM) and rat brain membranes as previously described . Incubations proceeded for 3−4 h at 25 °C in 10 mM Tris-HCl, pH 7.4, containing 100 mM choline chloride, 3 mM MnCl 2 , and 100 nM DAMGO to block binding to μ sites and PIC.…”

Section: Methodsmentioning

confidence: 99%

“…δ binding sites were labeled using [ 3 H]DADLE (1.7-2.5 nM) and rat brain membranes as previously described. 14 Incubations proceeded for 3-4 h at 25 °C in 10 mM Tris-HCl, pH 7.4, containing 100 mM choline chloride, 3 mM MnCl2, and 100 nM DAMGO to block binding to µ sites and PIC. Nonspecific binding was determined using 20 µM levallorphan.…”

Section: -(1234511-hexahydro-3-methyl-26-methano-10methoxy-6h-azocino...mentioning

confidence: 99%

Probes for Narcotic Receptor-Mediated Phenomena. 21. Novel Derivatives of 3-(1,2,3,4,5,11-Hexahydro-3-methyl-2,6-methano-6H-azocino[4,5-b]indol-6-yl)- phenols with Improved δ Opioid Receptor Selectivity

Bertha¹,

Ellis²,

Flippen‐Anderson³

et al. 1996

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

Derivatives of racemic and optically pure levorotatory 3-(1,2,3,4,5,11-hexahydro-3-methyl-2,6-methano-6H-azocino[4,5-b]in dol-6-yl)phenols containing methoxy substituents in the C10', C9', and C8' positions (compounds 9-11, respectively) were synthesized and characterized by spectroscopic and X-ray methods. The binding affinities for the mu, delta and kappa 1 opioid receptors and activity in the guinea pig ileum (GPI) and mouse vas deferens (MVD) functional bioassays were determined for these compounds. A methoxy substituent in the C8' position decreases the binding affinity for both the mu and delta receptors, while a C10' methoxy substituent has little effect on either binding affinity. Interestingly, a methoxy group at the C9' position in the levorotatory series provides compound (-)-10 which exhibits both enhanced in vitro affinity and selectivity for the delta opioid receptor relative to the unsubstituted derivative (-)-8 and is the most selective (mu/delta IC50 ratio 17.9, kappa 1/delta IC50 ratio 314) and highest affinity (IC50 3.7 nM) delta receptor ligand for this novel class of compounds. The results of the GPI and MVD bioassays are more dramatic and indicate that (-)-10 is an agonist for the delta receptor (IC50 49.0 nM) with substantial selectivity for the delta versus the mu receptor borne out by a GPI/MVD IC50 ratio of > 612.

show abstract

Interaction of β‐funaltrexamine with [³H]cycloFOXY binding in rat brain: Further evidence that β‐FNA alkylates the opioid receptor complex

Rothman

Bykov

Mahboubi

et al. 1991

Synapse

Self Cite

View full text Add to dashboard Cite

beta-Funaltrexamine (beta-FNA) is an alkylating derivative of naltrexone. In addition to acting as an irreversible inhibitor of mu-receptor-mediated physiological effects, intracerebroventricular (i.c.v.) administration of beta-FNA to rat attenuates the ability of selective delta receptor antagonists and naloxone to reverse delta receptor-mediated effects. Moreover, recent work demonstrated that i.c.v. administration of beta-FNA alters the conformation of the opioid receptor complex, as inferred by a decrease in the Bmax of the lower affinity [3H][D-ala2,D-leu5]enkephalin binding site. Consistent with the decreased potency of naloxone as an inhibitor of delta receptor mediated effects, beta-FNA doubled the naloxone IC50 for displacing [3H][D-ala2,D-leu5]enkephalin from its lower affinity binding site. These data collectively support the hypothesis that the opioid receptor complex postulated to mediate mu-delta interactions in vivo is identical to the opioid receptor complex as defined by vitro ligand binding studies. A direct prediction of this hypothesis is that beta-FNA should increase the Kd of antagonists for the mu binding site (mu cx) of the receptor complex. The data reported in this paper demonstrate that beta-FNA doubled the IC50 of the potent narcotic antagonist, 6-desoxy-6 beta-fluoronaltrexone (cycloFOXY) for displacing [3H][D-ala2,D-leu5]enkephalin from its lower affinity binding site, and doubled the Kd of [3H]cycloFOXY for its mu binding site, providing additional data that the mu binding site labeled by [3H]cycloFOXY is the mu binding site of the opioid receptor complex. beta-FNA also altered the kappa binding site labeled by [3H]cycloFOXY, and when administered intrathecally to mice, beta-FNA produced a longlasting antinociception in the acetic acid writhing test.

show abstract

LY164929: a highly selective ligand for the lower affinity [3H]D-Ala2-D-Leu-5-enkephalin binding site

Cited by 31 publications

References 15 publications

Probes for Narcotic Receptor-Mediated Phenomena. 25. Synthesis and Evaluation ofN-Alkyl-Substituted (α-Piperazinylbenzyl)benzamides as Novel, Highly Selective δ Opioid Receptor Agonists

Probes for Narcotic Receptor-Mediated Phenomena. 25. Synthesis and Evaluation ofN-Alkyl-Substituted (α-Piperazinylbenzyl)benzamides as Novel, Highly Selective δ Opioid Receptor Agonists

Probes for Narcotic Receptor-Mediated Phenomena. 21. Novel Derivatives of 3-(1,2,3,4,5,11-Hexahydro-3-methyl-2,6-methano-6H-azocino[4,5-b]indol-6-yl)- phenols with Improved δ Opioid Receptor Selectivity

Interaction of β‐funaltrexamine with [³H]cycloFOXY binding in rat brain: Further evidence that β‐FNA alkylates the opioid receptor complex

Contact Info

Product

Resources

About

LY164929: a highly selective ligand for the lower affinity [3H]D-Ala2-D-Leu-5-enkephalin binding site

Cited by 31 publications

References 15 publications

Probes for Narcotic Receptor-Mediated Phenomena. 25. Synthesis and Evaluation ofN-Alkyl-Substituted (α-Piperazinylbenzyl)benzamides as Novel, Highly Selective δ Opioid Receptor Agonists

Probes for Narcotic Receptor-Mediated Phenomena. 25. Synthesis and Evaluation ofN-Alkyl-Substituted (α-Piperazinylbenzyl)benzamides as Novel, Highly Selective δ Opioid Receptor Agonists

Probes for Narcotic Receptor-Mediated Phenomena. 21. Novel Derivatives of 3-(1,2,3,4,5,11-Hexahydro-3-methyl-2,6-methano-6H-azocino[4,5-b]indol-6-yl)- phenols with Improved δ Opioid Receptor Selectivity

Interaction of β‐funaltrexamine with [3H]cycloFOXY binding in rat brain: Further evidence that β‐FNA alkylates the opioid receptor complex

Contact Info

Product

Resources

About

Interaction of β‐funaltrexamine with [³H]cycloFOXY binding in rat brain: Further evidence that β‐FNA alkylates the opioid receptor complex