Novel small molecule alpha9 alpha10 nicotinic receptor antagonists for pain management

Holtman, Joseph R.; Dwoskin, Linda P.; Wala, Elzbieta P.; Crooks, Peter A.; McIntosch, J.

doi:10.1016/j.jpain.2010.01.138

Cited by 4 publications

(9 citation statements)

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“…17,18 These analogs demonstrated effectiveness against persistent inflammatory pain and posttraumatic neuropathy at doses well below those that produced motor dysfunction in rats. 17,19 However, they were not investigated in chemotherapy-evoked pain. In order to test this possibility the most potent and α9α10-selective agent from the bis - group, ZZ1-61C, was characterized in a rat model of vincristine-induced neuropathy.…”

Section: Introductionmentioning

confidence: 99%

Novel Small Molecule α9α10 Nicotinic Receptor Antagonist Prevents and Reverses Chemotherapy-Evoked Neuropathic Pain in Rats

Wala¹,

Crooks

McIntosh

et al. 2012

Anesthesia &Amp; Analgesia

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Background Peripheral neuropathy is a common dose-limiting side effect of chemotherapy. There are no clinically proven analgesics for the treatment of this condition. Drugs from different classes have been tested with mixed results. Identification of novel molecular targets for analgesic(s) is important. Antagonism of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype (absent in brain) is thought to underlie analgesic efficacy of peptide α-conotoxins. We found novel non-peptide small molecule analogs from a family of tetrakis-, tris- and bis-azaaromatic quaternary ammonium salts (high potency with selectivity as antagonists at the α9α10 nAChRs) to produce dose-related analgesia in rat models of nerve injury-evoked neuropathy and persistent inflammatory pain. No tests were done in a model of neuropathy induced by drug administration (i.e., chemotherapy). Methods In this study, a lead bis-analog, ZZ1-61c, was characterized in a rat model of vincristine-evoked neuropathy. Male Sprague-Dawley rats were repeatedly dosed with the vinca-alkaloid, vincristine (100 µg/kg/day IP, days 1–5 and 8–12). ZZ1-61c (100 µg/kg/day IP) was given either along with or after completion of vincristine (commencing by day 15 when neuropathy was maximum). Responsiveness was assessed with von Frey hairs and the paw-pressure test. The effects of ZZ1-61c on motor function (rotarod) and muscle strength (grip test) were characterized in naïve rats. Results The development of neuropathy was demonstrated with repeated dosing of vincristine (pain hypersensitivity in response to mechanical stimulation). ZZ1-61c showed both preventive and restorative effects on this condition: 1) vincristine-evoked sensitivity to pressure was reduced by co-administration of ZZ1-61c; 2) established neuropathy was diminished by ZZ1-61c after cessation of chemotherapy. ZZ-1-61c did not cause motor dysfunction (rotarod) or muscular weakness (the grip test). Conclusions This study suggests that ZZ1-61c, a novel compound with a unique mechanism of antagonistic action at the α9α10 nAChR, may be a potential drug candidate for prevention and attenuation of neuropathic pain resulting from chemotherapy. Such a strategy may provide effective treatment which circumvents toxicity of centrally acting agonists at nAChR.

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Section: Introductionmentioning

confidence: 99%

Novel Small Molecule α9α10 Nicotinic Receptor Antagonist Prevents and Reverses Chemotherapy-Evoked Neuropathic Pain in Rats

Wala¹,

Crooks

McIntosh

et al. 2012

Anesthesia &Amp; Analgesia

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“…20 In this context, it is remarkable that analogs from a family of tetrakis-tris-and bis-quaternary ammonium salts (lead compounds highly selective for α9α10 nAChR) alleviated signs of pain hypersensitivity that was derived from neurotoxicity or nerve trauma; in that, partial reversal of pain hypersensitivity in vincristine treated rats (present study) was comparable to what was previously seen in rats with chronic nerve injury. 19,42 They also blocked, in a dose-related manner, formalin-evoked flinching (a late phase, which is thought to involve central sensitization) in a rat model of persistent inflammatory pain. None of them was active in a rat model of acute nociception (tail-flick test) suggesting a limited role of α9α10 in this type of pain.…”

Section: Discussionmentioning

confidence: 93%

“…33,[37][38][39] Fourth, strikingly, the pain-enhancing effect of vincristine was comparable in magnitude to that seen after chronic constriction nerve injury (reduction VT ~ 80 g, the paw pressure test). 19,27,40 Even though behavioral outcomes appear similar, the mechanisms are thought to be somewhat distinct in these pain models (i.e., axonal degeneration in peripheral nerves accompanies painful neuropathy secondary to nerve trauma but not chemotherapy). [22][23][24] From a pain treatment perspective, drugs that modify cellular calcium levels were effective against pain sensitization caused by toxic but not traumatic nerve insult.…”

Section: Discussionmentioning

confidence: 99%

“…None of them was active in a rat model of acute nociception (tail-flick test) suggesting a limited role of α9α10 in this type of pain. 17,19,42 Activation of central α4β2 (and to lesser extent α7) subunits nAChR have been associated with analgesic effects of nicotinic agonists. [3][4][5][6] Nevertheless, peptides α-conotoxins (Vc1, RgIA) that act as antagonists at α9α10 nAChR also show analgesic activities in rodent models of neuropathy (chronic constriction nerve injury, spinal nerve ligation, diabetes) and inflammation (complete Freud's adjuvant).…”

Section: Discussionmentioning

confidence: 99%

“…17,18 These analogs demonstrated effectiveness against persistent inflammatory pain and posttraumatic neuropathy at doses well below those that produced motor dysfunction in rats. 17,19 However, they were not investigated in chemotherapy-evoked pain. In order to test this possibility the most potent and α9α10-selective agent from the bisgroup, ZZ1-61C, was characterized in a rat model of vincristine-induced neuropathy.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Novel small molecule alpha9 alpha10 nicotinic receptor antagonist prevents and reverses chemotherapy evoked neuropathic pain in rats

Wala¹,

Crooks²,

McIntosch³

et al. 2011

The Journal of Pain

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Discovery of non-peptide, small molecule antagonists of α9α10 nicotinic acetylcholine receptors as novel analgesics for the treatment of neuropathic and tonic inflammatory pain

Zheng

Zhang

Dowell

et al. 2011

Bioorganic & Medicinal Chemistry Letters

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A series of azaaromatic quaternary ammonium analogs has been discovered as potent and selective α9α10 nicotinic acetylcholine receptor (nAChR) antagonists. The preliminary structure-activity relationships of these analogs suggest that increased rigidity in the linker units results in higher potency in inhibition of α9α10 nAChRs and greater selectivity over α7 nAChRs. These analogs represent a new class of analgesic for the treatment of neuropathic and tonic inflammatory pain.

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Novel small molecule alpha9 alpha10 nicotinic receptor antagonists for pain management

Cited by 4 publications

References 0 publications

Novel Small Molecule α9α10 Nicotinic Receptor Antagonist Prevents and Reverses Chemotherapy-Evoked Neuropathic Pain in Rats

Novel Small Molecule α9α10 Nicotinic Receptor Antagonist Prevents and Reverses Chemotherapy-Evoked Neuropathic Pain in Rats

Novel small molecule alpha9 alpha10 nicotinic receptor antagonist prevents and reverses chemotherapy evoked neuropathic pain in rats

Discovery of non-peptide, small molecule antagonists of α9α10 nicotinic acetylcholine receptors as novel analgesics for the treatment of neuropathic and tonic inflammatory pain

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