The analgesic-like properties of the alpha7 nAChR silent agonist NS6740 is associated with non-conducting conformations of the receptor

Papke, Roger L.; Bağdaş, Deniz; Kulkarni, Abhijit; Gould, Timothy M.; AlSharari, Shakir D.; Thakur, Ganesh A.; Damaj, M. Imad

doi:10.1016/j.neuropharm.2014.12.002

Cited by 76 publications

(151 citation statements)

References 18 publications

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“…Although the activation of α-7-nACh receptor has been reported as anti-inflammatory and protective against nociception in neuropathic pain [262][263][264][265], it is unlikely that the analgesic proprieties of CBD are mediated by this receptor as CBD tends to antagonize (IC 50 = 12.7 μM) its action in vitro [27].…”

Section: Cbd Receptor Targets In Painmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

409

298

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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Section: Cbd Receptor Targets In Painmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

409

298

View full text Add to dashboard Cite

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“…How this property of bisbalol can contribute to nAChR activity in immune cells is unclear and future studies in immune cells will be required to address the role of this compound on cholinergic immunity. It is plausible that the inhibitory actions of bisabolol on α7-nAChR channels may promote an intracellular anti-inflammatory signaling response by α7-nAChR in a non-ionotropic ways (Clark et al, 2014;Papke et al, 2014). Our electrophysiological studies suggest that bisabolol interacts with the closed state of the receptor while published studies by others have shown that immune cells do not display nAChR currents (for a review, Papke, 2014).…”

Section: Discussionmentioning

confidence: 67%

Inhibitory actions of bisabolol on α7-nicotinic acetylcholine receptors

et al. 2015

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“…Of course, even a partial agonist with low channel activation efficacy may still be quite effective at inducing structural changes associated with the desensitized conformations of the receptor (44), and this has led to the hypothesis that ␣7 function, especially in non-neuronal cells incapable of ion-channel signaling, may be due to the ability of orthosteric ligands to induce global changes in receptor structure that can be transmitted to the receptor's protein interactome (45,46) and accomplish metabotropic type signaling (47-49). The potential importance for signaling through non-conducting states is also supported by the identification of silent agonists (50) such as NS6740 (51,52), which has been shown to be a very effective analgesic in several models of inflammatory or neuropathic pain (53), although its primary effect on channel activity is desensitization.…”

Section: Discussionmentioning

confidence: 99%

Critical Molecular Determinants of α7 Nicotinic Acetylcholine Receptor Allosteric Activation

Horenstein

Papke

Kulkarni

et al. 2016

Journal of Biological Chemistry

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The ␣7 nicotinic acetylcholine receptors (nAChRs) are uniquely sensitive to selective positive allosteric modulators (PAMs), which increase the efficiency of channel activation to a level greater than that of other nAChRs. Although PAMs must work in concert with "orthosteric" agonists, compounds such as GAT107 ((3aR,4S,9bS)-4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) have the combined properties of agonists and PAMs (ago-PAM) and produce very effective channel activation (direct allosteric activation (DAA)) by operating at two distinct sites in the absence of added agonist. One site is likely to be the same transmembrane site where PAMs like PNU-120596 function. We show that the other site, required for direct activation, is likely to be solventaccessible at the extracellular domain vestibule. We identify key attributes of molecules in this family that are able to act at the DAA site through variation at the aryl ring substituent of the tetrahydroquinoline ring system and with two different classes of competitive antagonists of DAA. Analyses of molecular features of effective allosteric agonists allow us to propose a binding model for the DAA site, featuring a largely non-polar pocket accessed from the extracellular vestibule with an important role for Asp-101. This hypothesis is supported with data from sitedirected mutants. Future refinement of the model and the characterization of specific GAT107 analogs will allow us to define critical structural elements that can be mapped onto the receptor surface for an improved understanding of this novel way to target ␣7 nAChR therapeutically.The ␣7 nicotinic acetylcholine receptor (nAChR) 3 is a recognized target for both central nervous system disorders, such as Alzheimer disease and schizophrenia, and peripheral indications, such as inflammation and associated pain (1, 2). As with other nicotinic receptors, conventional thinking has focused on the function of ␣7 as a ligand-gated ion channel that is activated by the transmitter acetylcholine (ACh). However, this traditional perspective has been challenged and enlarged upon by numerous observations. First, ␣7 receptors can be activated by choline as well as ACh (3), removing it from the position of being strictly optimized for synaptic function and suggesting that it may respond to tissue factors, especially in the context of playing a role in the modulation of inflammation (4). Additional insights have come from the exploration of the rich pharmacology of this receptor, beginning with the identification of a variety of selective agonists and partial agonists that control the conformational dynamics of activation and desensitization in ways that are totally unlike the behavior of other nAChRs, such as those of the neuromuscular junction and autonomic ganglia that are clearly optimized for fast synaptic transmission (1, 5). To a large degree, the specializations of synaptic nAChR arise from the evolution of different types of subunits that create the ACh-binding site at the interfa...

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The analgesic-like properties of the alpha7 nAChR silent agonist NS6740 is associated with non-conducting conformations of the receptor

Cited by 76 publications

References 18 publications

Molecular Targets of Cannabidiol in Neurological Disorders

Molecular Targets of Cannabidiol in Neurological Disorders

Inhibitory actions of bisabolol on α7-nicotinic acetylcholine receptors

Critical Molecular Determinants of α7 Nicotinic Acetylcholine Receptor Allosteric Activation

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