Epibatidine: a novel (chloropyridyl)azabicycloheptane with potent analgesic activity from an Ecuadoran poison frog

Spande, Thomas F.; Garraffo, H. Martin; Edwards, M. W.; Yeh, Herman J. C.; Pannell, Lewis K.; Daly, John W.

doi:10.1021/ja00035a048

Cited by 539 publications

(326 citation statements)

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“…Most pain medications fall under two classes of compounds, opioids and nonsteroidal antiinflammatory drugs. Recently, structural analogs of nicotine have also demonstrated strong analgesic potency (1,2). Although these agents may provide alternate pain therapies, a number of issues remain to be resolved, such as addictive profiles and side effects, including paradoxical hyperalgesia.…”

mentioning

confidence: 99%

Short- and long-term enhancement of excitatory transmission in the spinal cord dorsal horn by nicotinic acetylcholine receptors

Genzen

McGehee

2003

Proc. Natl. Acad. Sci. U.S.A.

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Spinal administration of nicotinic agonists can produce both hyperalgesic and analgesic effects in vivo. The cellular mechanisms underlying these behavioral phenomena are not understood. As a possible explanation for nicotinic hyperalgesia, we tested whether nicotinic acetylcholine receptors (nAChRs) could enhance excitatory transmission onto spinal cord dorsal horn neurons. Whole-cell patch-clamp recordings were performed in neonatal rat spinal cord slices. Activation of nAChRs enhanced glutamatergic synaptic transmission in 59% of dorsal horn neurons tested, and this effect was blocked by methyllycaconitine (10 nM), suggesting a key role for ␣7 nAChRs. Inhibition of acetylcholinesterase with methamidophos also enhanced transmission, demonstrating a similar effect of endogenous acetylcholine. nAChR activation also enhanced transmission by dorsal root entry zone stimulation, suggesting that ␣7 nAChRs on the central terminals of DRG afferents mediate this effect. Paired pre-and postsynaptic stimulation induced long-term potentiation of excitatory inputs to some of the dorsal horn neurons. Long-term potentiation induction was much more prevalent when nicotine was applied during stimulation. This effect also depended on both ␣7 nAChRs and N-methyl-D-aspartate glutamate receptors. Our findings demonstrate that ␣7 nAChRs can contribute to both short-and long-term enhancement of glutamatergic synaptic transmission in the spinal cord dorsal horn and provide a possible mechanism for nicotinic hyperalgesia.E ffective pain management is a major challenge for modern healthcare. Most pain medications fall under two classes of compounds, opioids and nonsteroidal antiinflammatory drugs. Recently, structural analogs of nicotine have also demonstrated strong analgesic potency (1, 2). Although these agents may provide alternate pain therapies, a number of issues remain to be resolved, such as addictive profiles and side effects, including paradoxical hyperalgesia. Considerable research has focused on the analgesic effects of nicotine and its analogs (2-7), yet the mechanisms underlying nicotinic hyperalgesia are not well understood.Hyperalgesia and͞or irritation have been observed after central injections of nicotinic agonists (8-10), systemic injections of subanalgesic doses (11), and intrathecal applications (12,13). This intrathecal effect is associated with significant increases in excitatory transmitter release (14), and both nicotinic and glutamate receptor antagonists can decrease this hyperalgesia (15, 16). Although dorsal horn neurons are excited by nicotine (17), it is not known which subtypes of nicotinic acetylcholine receptors (nAChRs) are expressed by dorsal horn neurons or on presynaptic afferent terminals. For example, nicotinic enhancement of synaptic activity has been noted in the spinal cord dorsal horn (SCDH) in mice that lack the ␣4 nAChR subunit, but the nAChR subtype(s) that mediate this effect is unknown (5).Neuronal nAChRs are pentameric ligand-gated ion channels, and molecular cloning has identified nin...

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confidence: 99%

Short- and long-term enhancement of excitatory transmission in the spinal cord dorsal horn by nicotinic acetylcholine receptors

Genzen

McGehee

2003

Proc. Natl. Acad. Sci. U.S.A.

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“…We report here the isolation and identification of the gene cluster for nicotine degradation in P. putida S16. HSP and DHP in the Pseudomonas pathway are two important precursors for synthesis of drugs such as analogues of epibatidine, an (24,27,34,36,40). The genetic organization of nicotine degradation gene cluster of strain S16 is distinctive and contains three ORFs.…”

Section: Discussionmentioning

confidence: 99%

A Novel Gene, Encoding 6-Hydroxy-3-Succinoylpyridine Hydroxylase, Involved in Nicotine Degradation by Pseudomonas putida Strain S16

Tang

Wang

et al. 2008

Appl Environ Microbiol

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Previous research suggested that Pseudomonas spp. may attack the pyrrolidine ring of nicotine in a way similar to mammalian metabolism, resulting in the formation of pseudooxynicotine, the direct precursor of a potent tobacco-specific lung carcinogen. In addition, the subsequent intermediates, 6-hydroxy-3-succinoylpyridine (HSP) and 2,5-dihydroxypyridine (DHP) in the Pseudomonas nicotine degradation pathway are two important precursors for drug syntheses. However, there is little information on the molecular mechanism for nicotine degradation via the pyrrolidine pathway until now. In this study we cloned and sequenced a 4,879-bp gene cluster involved in nicotine degradation. Intermediates N-methylmyosmine, pseudooxynicotine, 3-succinoylpyridine, HSP, and DHP were identified from resting cell reactions of the transformant containing the gene cluster and shown to be identical to those of the pyrrolidine pathway reported in wild-type strain Pseudomonas putida S16. The gene for 6-hydroxy-3-succinoylpyridine hydroxylase (HSP hydroxylase) catalyzing HSP directly to DHP was cloned, sequenced, and expressed in Escherichia coli, and the purified HSP hydroxylase (38 kDa) is NADH dependent. DNA sequence analysis of this 936-bp fragment reveals that the deduced amino acid shows no similarity with any protein of known function.

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“…It was found to be at least 200 times more potent than morphine in bioassays of analgesic-like effects in mice, but its effects were not blocked by the opiate receptor antagonist naloxone. 1,[3][4][5] Due to its outstanding pharmacological activity, unique structure, and scarcity in nature, epibatidine has been the subject of many biological [3][4][5][6][7][8][9][10][11] and synthetic studies. 12,13 The strategies reported for the synthesis of this novel alkaloid primarily focused on the synthesis of the racemic form although the optically active epibatidine can be obtained by involving an optical resolution step at an appropriate stage.…”

Section: Introductionmentioning

confidence: 99%

Asymmetric hydroarylation of hetero-atom containing norbornene derivatives and enantioselective synthesis of analogs of epibatidine

Li¹,

Tang²,

Xu³

et al. 2002

Arkivoc

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Epibatidine: a novel (chloropyridyl)azabicycloheptane with potent analgesic activity from an Ecuadoran poison frog

Cited by 539 publications

References 0 publications

Short- and long-term enhancement of excitatory transmission in the spinal cord dorsal horn by nicotinic acetylcholine receptors

Short- and long-term enhancement of excitatory transmission in the spinal cord dorsal horn by nicotinic acetylcholine receptors

A Novel Gene, Encoding 6-Hydroxy-3-Succinoylpyridine Hydroxylase, Involved in Nicotine Degradation by Pseudomonas putida Strain S16

Asymmetric hydroarylation of hetero-atom containing norbornene derivatives and enantioselective synthesis of analogs of epibatidine

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