Narcotic antagonists in the benzomorphan series

Harris, Louis S.

doi:10.1007/bf00246889

Cited by 179 publications

(106 citation statements)

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“…Exchange of the cyclopropylmethyl moiety of burprenorphine with cyclooctylmethyl lowered affinity at the μ receptor by one order of magnitude but also increased the efficacy substantially, producing essentially a full agonist. This is consistent with results in other fused-ring opiate families, in which substitution of the N-CH 3 with cyclopropylmethyl or allyl substituents leads to antagonist activity while incorporation of a larger moiety, such as phenethyl, restores agonist activity (Harris and Pierson, 1964). As with buprenorphine, introduction of the cyclooctylmethyl into fentanyl (to make SR 14134) and carfentanil (to make SR14143) decreases their μ receptor affinity by one order of magnitude, but in contrast, it converts these compounds into low efficacy partial agonists, on the order of buprenorphine (Table 3).…”

Section: Discussionsupporting

confidence: 90%

Characterization of opiates, neuroleptics, and synthetic analogs at ORL1 and opioid receptors

Zaveri

Polgar

Olsen

et al. 2001

European Journal of Pharmacology

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Nociceptin/orphanin FQ (N/OFQ) was recently identified as the endogenous ligand for the opioidreceptor like (ORL1) receptor. Although the ORL1 receptor shows sequence homology with the opioid receptors, the nociceptin/ORL1 ligand-receptor system has very distinct pharmacological actions compared to the opioid receptor system. Recently, several small-molecule ORL1 receptor ligands were reported by pharmaceutical companies. Most of these ligands had close structural similarities with known neuroleptics and opiates. In this study, we screened several available neuroleptics and opiates for their binding affinity and functional activity at ORL1 and the opioid receptors. We also synthesized several analogs of known opiates with modified piperidine Nsubstituents in order to characterize the ORL1 receptor ligand binding pocket. Substitution with the large, lipophilic cyclooctylmethyl moiety increased ORL1 receptor affinity and decreased μ receptor affinity and efficacy in the fentanyl series of ligands but had a different effect in the oripavine class of opiate ligands. Our results indicate that opiates and neuroleptics may be good starting points for ORL1 receptor ligand design, and the selectivity may be modulated by appropriate structural modifications.

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Section: Discussionsupporting

confidence: 90%

Characterization of opiates, neuroleptics, and synthetic analogs at ORL1 and opioid receptors

Zaveri

Polgar

Olsen

et al. 2001

European Journal of Pharmacology

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“…Dermorphin, dissolved in 0.1 ml of 0.9% w/v NaCl solution (saline), or saline alone (controls) was injected into the tail vein in groups of 10 male IRC mice, weighing 25-30 g. The extent of analgesia was expressed as percentage of antinociceptive effect, as described by Harris & Pierson (1964). With a two fold increase in latency of reaction time as a quantal index of inhibition, the median antinociceptive dose (ED50) and 95% confidence limits were calculated according to the method of Litchfield & Wilcoxon (1949).…”

Section: Methodsmentioning

confidence: 99%

Pharmacological Data on Dermorphins, a New Class of Potent Opioid Peptides From Amphibian Skin

Broccardo¹,

Erspamer²,

Falconieri³

et al. 1981

British J Pharmacology

326

136

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1 Dermorphin and Hyp';-dermorphin are the first representatives of a new class of potent opioid peptides occurring in amphibian skin. They present the unique feature of having a D-Ala residue incorporated in the peptide molecule. 2 Dermorphin displayed a potent depressive action on electrically stimulated contractions of the guinea-pig ileum and mouse vas deferens preparations. Dermorphin was respectively 57,294, 18 and 39 times more potent than Met-enkephalin, Leu-enkephalin, f8-endorphin, and morphine on the guinea-pig ileum opiate receptors. On the vas deferens receptors, dermorphin was about as potent as the enkephalins and 40 times more potent than morphine. Naloxone was a powerful antagonist to dermorphin in both preparations. 3 Dermorphin produced potent and long-lasting analgesia in mice by intravenous injection, and in rats by intracerebroventricular injection, the ED9() being here of the order of 13-23 pmol/rat. Morphine was 752 and 2170 times less potent, depending on the analgesia test used. At high intracerebroventricular doses analgesia was accompanied by catalepsy. 4 Intracerebroventricular infusion of dermorphin induced development of tolerance and precipitation of withdrawal symptoms upon administration of naloxone. Both tolerance and physical dependence were consistently less marked with dermorphin than with morphine. 5

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“…For each test time, the percentage maximum possible effect (%MPE) was calculated as (test latencyÀbaseline latency) Â (cutoff timeÀbaseline latency) À1 Â 100% (Harris & Pierson, 1964). %MPE values at the time point at which the greatest antinociceptive responses were observed for each respective 876…”

Section: Statistical Analysesmentioning

confidence: 99%

Synergistic and additive interactions of the cannabinoid agonist CP55,940 with μ opioid receptor and α₂‐adrenoceptor agonists in acute pain models in mice

Tham

Angus

Tudor

et al. 2005

British J Pharmacology

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1 Cannabinoid receptor agonists elicit analgesic effects in acute and chronic pain states via spinal and supraspinal pathways. We investigated whether the combination of a cannabinoid agonist with other classes of antinociceptive drugs exerted supra-additive (synergistic) or additive effects in acute pain models in mice. 2 The interactions between the cannabinoid agonist CP55,940, a 2 -adrenoceptor agonist dexmedetomidine and m-opioid receptor agonist morphine were evaluated by isobolographic analysis of antinociception in hot plate (551C) and tail flick assays in conscious male Swiss mice. Drug interactions were examined by administering fixed-ratio combinations of agonists (s.c.) in 1 : 1, 3 : 1 and 1 : 3 ratios of their respective ED 50 fractions. 3 CP55,940, dexmedetomidine and morphine all caused dose-dependent antinociception. In the hot plate and tail flick assays, ED 50 values (mg kg À1 ) were CP55,940 1.13 and 0.51, dexmedetomidine 0.066 and 0.023, and morphine 29.4 and 11.3, respectively. Synergistic interactions existed between CP55,940 and dexmedetomidine in the hot plate assay, and CP55,940 and morphine in both assays. Additive interactions were found for CP55,940 and dexmedetomidine in the tail flick assay, and dexmedetomidine and morphine in both assays. 4 Thus, an a 2 -adrenoceptor agonist or m opioid receptor agonist when combined with a cannabinoid receptor agonist showed significant synergy in antinociception in the hot plate test. However, for the tail flick nociceptive response to heat, only cannabinoid and m opioid receptor antinociceptive synergy was demonstrated. If these results translate to humans, then prudent selection of dose and receptorspecific agonists may allow an improved therapeutic separation from unwanted side effects.

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Narcotic antagonists in the benzomorphan series

Cited by 179 publications

References 3 publications

Characterization of opiates, neuroleptics, and synthetic analogs at ORL1 and opioid receptors

Characterization of opiates, neuroleptics, and synthetic analogs at ORL1 and opioid receptors

Pharmacological Data on Dermorphins, a New Class of Potent Opioid Peptides From Amphibian Skin

Synergistic and additive interactions of the cannabinoid agonist CP55,940 with μ opioid receptor and α₂‐adrenoceptor agonists in acute pain models in mice

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Narcotic antagonists in the benzomorphan series

Cited by 179 publications

References 3 publications

Characterization of opiates, neuroleptics, and synthetic analogs at ORL1 and opioid receptors

Characterization of opiates, neuroleptics, and synthetic analogs at ORL1 and opioid receptors

Pharmacological Data on Dermorphins, a New Class of Potent Opioid Peptides From Amphibian Skin

Synergistic and additive interactions of the cannabinoid agonist CP55,940 with μ opioid receptor and α2‐adrenoceptor agonists in acute pain models in mice

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Synergistic and additive interactions of the cannabinoid agonist CP55,940 with μ opioid receptor and α₂‐adrenoceptor agonists in acute pain models in mice