Structural Determinants of Efficacy for κ Opioid Receptors in the Orvinol Series:  7,7-Spiro Analogues of Buprenorphine

Husbands, Stephen M.; Lewis, John W.

doi:10.1021/jm991165p

Cited by 20 publications

(29 citation statements)

References 7 publications

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“…As predicted, based on earlier work by ourselves and others, 16,17,27 the N -cyclopropylmethylnororvinols synthesized and evaluated in this study had very high affinity but little to no MOR/KOR selectivity in binding assays. Also as predicted, in the [ 35 S]GTPγS assay used to determine the level of agonist activity at each receptor, the majority of the ligands were KOR agonists with lower efficacy at the MOR.…”

Section: Discussionsupporting

confidence: 82%

Orvinols with Mixed Kappa/Mu Opioid Receptor Agonist Activity

et al. 2013

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Dual-acting kappa opioid receptor (KOR) agonist and mu opioid receptor (MOR) partial agonist ligands have been put forward as potential treatment agents for cocaine and other psychostimulant abuse. Members of the orvinol series of ligands are known for their high binding affinity to both KOR and MOR, but efficacy at the individual receptors has not been thoroughly evaluated. In this study, it is shown that a predictive model for efficacy at KOR can be derived, with efficacy being controlled by the length of the group attached to C20 and by the introduction of branching into the side chain. In vivo evaluation of two ligands with the desired in vitro profile confirms both display KOR, and to a lesser extent MOR, activity in an analgesic assay suggesting that, in this series, in vitro measures of efficacy using the [35S]GTPγS assay are predictive of the in vivo profile.

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Section: Discussionsupporting

confidence: 82%

Orvinols with Mixed Kappa/Mu Opioid Receptor Agonist Activity

et al. 2013

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“…Similarly, 1f displayed KOP receptor partial agonist activity, suggesting that the introduction of the methylene group between C20 and the bulky substituent leads to a rise in KOP receptor activation, as would be predicted from earlier studies. 29,30 1f profiled as a partial agonist at each of the four receptors, with highest potency at MOP and KOP receptors. 1e had little to no efficacy at any receptor, and like the 1-chloro analogue ( 6b ) may prove to be a universal opioid and NOP receptor antagonist.…”

Section: Resultsmentioning

confidence: 99%

Structural Determinants of Opioid and NOP Receptor Activity in Derivatives of Buprenorphine

et al. 2011

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The unique pharmacological profile of buprenorphine has led to its considerable success as an analgesic and as a treatment agent for drug abuse. Activation of nociceptin/orphanin FQ peptide (NOP) receptors has been postulated to account for certain aspects of buprenorphine’s behavioural profile. In order to investigate the role of NOP activation further, a series of buprenorphine analogues has been synthesised with the aim of increasing affinity for the NOP receptor. Binding and functional assay data on these new compounds indicate that the area around C20 in the orvinols is key to NOP receptor activity, with several compounds displaying higher affinity than buprenorphine. One compound, 1b, was found to be a mu opioid receptor partial agonist of comparable efficacy to buprenorphine, but with higher efficacy at NOP receptors.

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“…Clearly the ethyl group does not provide the extra bulk around C20 that has been reported to minimize KOP receptor efficacy 13 but is more likely accessing the site below C8 previously identified as a region associated with KOP receptor activation. 24−26 …”

Section: Discussionmentioning

confidence: 99%

Selectively Promiscuous Opioid Ligands: Discovery of High Affinity/Low Efficacy Opioid Ligands with Substantial Nociceptin Opioid Peptide Receptor Affinity

et al. 2014

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Emerging clinical and preclinical evidence suggests that a compound displaying high affinity for μ, κ, and δ opioid (MOP, KOP, and DOP) receptors and antagonist activity at each, coupled with moderate affinity and efficacy at nociceptin opioid peptide (NOP) receptors will have utility as a relapse prevention agent for multiple types of drug abuse. Members of the orvinol family of opioid ligands have the desired affinity profile but have typically displayed substantial efficacy at MOP and or KOP receptors. In this study it is shown that a phenyl ring analogue (1d) of buprenorphine displays the desired profile in vitro with high, nonselective affinity for the MOP, KOP, and DOP receptors coupled with moderate affinity for NOP receptors. In vivo, 1d lacked any opioid agonist activity and was an antagonist of both the MOP receptor agonist morphine and the KOP receptor agonist ethylketocyclazocine, confirming the desired opioid receptor profile in vivo.

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Structural Determinants of Efficacy for κ Opioid Receptors in the Orvinol Series: 7,7-Spiro Analogues of Buprenorphine

Cited by 20 publications

References 7 publications

Orvinols with Mixed Kappa/Mu Opioid Receptor Agonist Activity

Orvinols with Mixed Kappa/Mu Opioid Receptor Agonist Activity

Structural Determinants of Opioid and NOP Receptor Activity in Derivatives of Buprenorphine

Selectively Promiscuous Opioid Ligands: Discovery of High Affinity/Low Efficacy Opioid Ligands with Substantial Nociceptin Opioid Peptide Receptor Affinity

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