Synthesis and pharmacology of 8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine and related compounds

Wentland, Mark P.; Albertson, Noel F.; Pierson, Anne K.

doi:10.1021/jm00175a013

Cited by 16 publications

(28 citation statements)

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“…These findings may explain why 8-CAC had a 10-fold lower ED 50 value than cyclazocine in the writhing assay. An earlier study showed that 8-amino-cyclazocine had an oral-to-parental ratio that was considerably better than the ratio observed with cyclazocine, suggesting that replacement of the 8-OH with a group that might not be metabolized as rapidly may increase the bioavailability of these compounds (Wentland et al, 1980). Future studies will address the bioavailability of 8-CAC.…”

Section: Discussionmentioning

confidence: 99%

“…Cyclazocine is O-glucuronidated in humans, which may account for its short duration of action (Wentland et al, 1980). In an attempt to retard this metabolic inactivation and increase its duration of action, we discovered that replacement of the 8-OH group in cyclazocine with an 8-NH 2 provided a novel compound, 8-aminocyclazocine, which had somewhat diminished antinociception potency in mice when delivered by the subcutaneous route but comparable with cyclazocine efficacy when delivered orally (Wentland et al, 1980).…”

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confidence: 97%

“…In an attempt to retard this metabolic inactivation and increase its duration of action, we discovered that replacement of the 8-OH group in cyclazocine with an 8-NH 2 provided a novel compound, 8-aminocyclazocine, which had somewhat diminished antinociception potency in mice when delivered by the subcutaneous route but comparable with cyclazocine efficacy when delivered orally (Wentland et al, 1980). In addition, it was hypothesized that 8-amino derivatives of cyclazocine and EKC would have a longer duration of action than cyclazocine because the 8-amino compound would be less prone to glucuronidation .…”

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8-Carboxamidocyclazocine: A Long-Acting, Novel Benzomorphan

Bidlack

Cohen²,

McLaughlin³

et al. 2002

J Pharmacol Exp Ther

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To obtain benzomorphans with a longer duration of action that may be potential therapeutics for treating cocaine abuse, 8-carboxamidocyclazocine was synthesized. The pharmacological properties of 8-carboxamidocyclazocine were compared with the parent compound cyclazocine. Changing the 8-hydroxyl group on cyclazocine to an 8-carboxamido group resulted in only a 2-fold decrease in the affinity of the compound for the -receptor, and no change in the affinity for the -opioid receptor, with both compounds having K i values of less than 1 nM, based on radioligand binding assays. In the guanosine 5Ј-O -(3-[35 S]thio)triphosphate ([ 35 S]GTP␥S) binding assay, the two compounds produced moderate stimulation of GTP binding to the human -and -receptors. When given by i.c.v. injection, the compounds produced less than 60% antinociception in the mouse 55°C warm-water tail-flick test. However, in the mouse writhing test, the compounds had high potency in producing antinociception. Antinociception induced by either 8-carboxamidocyclazocine or cyclazocine was mediated by both -and -opioid receptors. Cyclazocine acted as a -antagonist in addition to its agonist properties at the -receptor, as measured by the inhibition of morphine-induced antinociception. In contrast, 8-carboxamidocyclazocine did not inhibit morphine-induced antinociception, demonstrating that it was not a -opioid receptor antagonist in this assay. An i.p. injection of an ED 70 dose of 8-carboxamidocyclazocine produced antinociception that lasted for 15 h in contrast to cyclazocine, which produced antinociception, lasting 2 h. 8-Carboxamidocyclazocine is a novel, long-acting benzomorphan, which possesses pharmacological properties that are distinct from the properties of cyclazocine.

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confidence: 99%

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8-Carboxamidocyclazocine: A Long-Acting, Novel Benzomorphan

Bidlack

Cohen²,

McLaughlin³

et al. 2002

J Pharmacol Exp Ther

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“…Glucuronidation of cyclazocine may account for its short duration of action 13. In an attempt to retard metabolism and increase the duration of activity, the 8‐OH group of cyclazocine was replaced with a NH 2 group 13. The replacement of the 8‐OH with an 8‐NH 2 increased the bioavailability of the compound.…”

Section: Introductionmentioning

confidence: 99%

Partial Opioids: Medications for the Treatment of Pain and Drug Abuse

Bidlack¹,

McLaughlin²,

Wentland³

2000

Annals of the New York Academy of Sciences

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Pentazocine and cyclazocine are two benzomorphans that were synthesized by the late Sydney Archer in 1962. These benzomorphans were synthesized as part of an effort to develop analgesics with little or no abuse potential. Pentazocine is used as an analgesic, often in individuals who have sever pain or in those who have drug‐abuse problems. Cyclazocine is a low‐liability analgesic and potential therapeutic for the treatment of drug abuse. The risk of drug dependence is lower with the benzomorphans, which usually act as partial agonists at the μ opioid receptor and as κ agonists. In an attempt to synthesize analogs of cyclazocine with increased bioavailability and varying κ agonist and partial μ agonist properties, a series of 8‐amino derivatives of cyclazocine were synthesized. These compounds were characterized in radioligand binding assays for their affinity and selectivity for the μ, δ, and κ opioid receptors. Mouse antinociceptive tests were used to characterize the agonist and antagonist properties of each compound at the μ, δ and κ receptors.

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“…Ligands in the neutral and protonated forms, as well as in the complexes (associates) [27] 3.9 b [27] n/a [27] II (methadone) l.6 b [28] III (naloxone) 60 a [27] 0.008 e [27] 0.08 f [29] IV (naltrexone) n/a [32] 0.05 f [27] V: R=OH (cyclazocine) 0.1 a [28] 0.04 a [31] 0.019 g [28] 0 > 10 g [28] n/a f [35] XI: R=CH 2 CH 2 CH 3 (N-propylnormethazocine) 3.9 a [35] n/a f [35] 0.019 g [29] XII: R=CH 2 -CH=CH 2 (N-allylnormethazocine) n/a b [30] 0.047 g [29] XIII: R=CH 2 -CH=C(CH 3 ); * agonist activity relative to pentazocine (ED 50 c = 120 mg/kg [33]); ED 50 is the dose producing analgesic action in 50% of test animals; AD 50 is the dose decreasing by half the analgesic action of an agonist administered in the ED 50 .…”

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Electron properties of aryl moieties in agonists and antagonists of opioid receptors

et al. 2005

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The electron properties of aryl moieties in the molecules of opioid receptor agonists and antagonists are compared in terms of the normalized atomic contributions of electron density to the frontal boundary molecular orbitals. Ligands in the neutral and protonated forms, as well as in the "ligand -receptor fragment" complexes (associates), are considered. The electron properties of the aryl moiety depend on the order in which the active centers of its tyramine fragment interact with the complementary region of an opioid receptor. It is suggested that the electron properties of aryl moieties determine the affinity of molecules to opioid receptors but do not influence the level of internal activity of such ligands.

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Synthesis and pharmacology of 8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine and related compounds

Cited by 16 publications

References 0 publications

8-Carboxamidocyclazocine: A Long-Acting, Novel Benzomorphan

8-Carboxamidocyclazocine: A Long-Acting, Novel Benzomorphan

Partial Opioids: Medications for the Treatment of Pain and Drug Abuse

Electron properties of aryl moieties in agonists and antagonists of opioid receptors

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