Nicotinic acetylcholine receptors in separate brain regions exhibit different affinities for methyllycaconitine

Yum, L.; Wolf, Kathleen M.; Chiappinelli, Vincent A.

doi:10.1016/0306-4522(95)00531-5

Cited by 50 publications

(36 citation statements)

References 28 publications

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“…In light of this it could be predicted that MLA might reach the brain in concentrations that would act on other receptor subtypes. Finally, it has been demonstrated that MLA binds to an additional unidenti®ed site (Yum et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Mecamylamine but not the α7 receptor antagonist α‐bungarotoxin blocks sensitization to the locomotor stimulant effects of nicotine

Kempsill

Pratt

2000

British J Pharmacology

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1 The involvement of a7 receptors in the locomotor stimulant e ects of nicotine has been examined by determining the ability of intracerebroventricular (i.c.v.) administration of the a7 receptor antagonist a-bungarotoxin (a-bgt) to modify sensitization to the locomotor activating e ects of chronic nicotine. 2 Intracerebroventricular administration of a-bgt (0.02 ± 8 nmoles) produced a dose dependent increase in convulsive behaviour. At doses less than 1.0 nmole, minimal convulsive behaviour occurred but larger doses evoked convulsions in all rats which displayed a more rapid onset time as the dose increased. 3 The binding distribution of a7 receptors 20 min and 3 h following an i.c.v. administration of [ 125 I]-a-bgt (0.02 nmoles) revealed clear binding in the hippocampus, cingulate cortex and hypothalamus which was more intense after 3 h. 4 Rats chronically treated with nicotine (0.4 mg kg 71 ) and exposed to the locomotor activity apparatus daily acquired an increase in locomotor activity relative to the control group after 3 days of treatment which reached a maximum after 7 days of treatment and was maintained for the 2 week treatment period. 5 Pre-treatment with mecamylamine (1 mg kg 71 ) prevented the expression of the locomotor stimulant e ects of nicotine but pre-treatment with i.c.v. a-bgt (0.02 nmoles) did not a ect nicotineinduced changes in locomotor activity. 6 The results of this study support the conclusion that nicotinic receptors of the a4b2 subtype rather than the a7 subtype are important in mediating the expression of the locomotor stimulant e ects of nicotine.

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Section: Discussionmentioning

confidence: 99%

Mecamylamine but not the α7 receptor antagonist α‐bungarotoxin blocks sensitization to the locomotor stimulant effects of nicotine

Kempsill

Pratt

2000

British J Pharmacology

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“…The plant alkaloid methyllycaconitine (MLA) is a hexacyclic norditerpenoid with a well-documented high-affinity, competitive antagonism for ␣7 nAChRs (Ward et al, 1990). However, MLA also acts as a competitive antagonist on other nAChR subtypes, including ␣3␤4 nAChRs Free et al, 2002Free et al, , 2003 and ␣4␤2 nAChRs (Yum et al, 1996), albeit with lower affinity. This activity of MLA on multiple neuronal nAChR subtypes suggests that MLA analogs could be used to elucidate structural determinants important for activity on specific nAChR subtypes.…”

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confidence: 99%

Analogs of Methyllycaconitine as Novel Noncompetitive Inhibitors of Nicotinic Receptors: Pharmacological Characterization, Computational Modeling, and Pharmacophore Development

McKay¹,

Chang²,

González-Cestari³

et al. 2007

Mol Pharmacol

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As a novel approach to drug discovery involving neuronal nicotinic acetylcholine receptors (nAChRs), our laboratory targeted nonagonist binding sites (i.e., noncompetitive binding sites, negative allosteric binding sites) located on nAChRs. Cultured bovine adrenal cells were used as neuronal models to investigate interactions of 67 analogs of methyllycaconitine (MLA) on native ␣3␤4* nAChRs. The availability of large numbers of structurally related molecules presents a unique opportunity for the development of pharmacophore models for noncompetitive binding sites. Our MLA analogs inhibited nicotinemediated functional activation of both native and recombinant ␣3␤4* nAChRs with a wide range of IC 50 values (0.9 -115 M). These analogs had little or no inhibitory effects on agonist binding to native or recombinant nAChRs, supporting noncompetitive inhibitory activity. Based on these data, two highly predictive 3D quantitative structure-activity relationship (comparative molecular field analysis and comparative molecular similarity index analysis) models were generated. These computational models were successfully validated and provided insights into the molecular interactions of MLA analogs with nAChRs. In addition, a pharmacophore model was constructed to analyze and visualize the binding requirements to the analog binding site. The pharmacophore model was subsequently applied to search structurally diverse molecular databases to prospectively identify novel inhibitors. The rapid identification of eight molecules from database mining and our successful demonstration of in vitro inhibitory activity support the utility of these computational models as novel tools for the efficient retrieval of inhibitors. These results demonstrate the effectiveness of computational modeling and pharmacophore development, which may lead to the identification of new therapeutic drugs that target novel sites on nAChRs.The physiological roles of neuronal nicotinic acetylcholine receptors (nAChRs) in synaptic release of acetylcholine and their involvement in the modulation of other important neurotransmitters such as norepinephrine, serotonin, GABA, glutamate, and dopamine make nAChRs prime targets for therapeutic interventions. In addition, nAChRs have been linked to pain, epilepsy, and many neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, and psychiatric disorders, such as depression and schizophrenia. The development of new drugs to target these receptors has been slow for several reasons: 1) multiple subtypes of nAChRs are expressed in the central and peripheral nervous systems; 2) few drugs are available that selectively target nAChR subtypes; and 3) information on the physiological roles of specific nAChR subtypes is limited. A key approach to provide a better understanding of physiological processes and pathophysiological conditions involving

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“…It is noteworthy that both DH␤E and erysodine exhibit low affinity to ␣7 nAChRs. Methyllycaconitine, which is another known competitive antagonist of ␣4␤2 nAChRs, is 50-to 100-fold more selective for ␣7 than for ␣4␤2 nAChRs (Yum et al, 1996) and possesses significantly higher affinity for ␣6␤2 than for ␣4␤2 nAChRs (Zoli et al, 2002). The pyridinyl ether A-186253 is a recently reported compound with markedly higher binding affinity for ␣4␤2 versus ␣3␤4 and ␣7 nAChRs, but it seems to exhibit low functional selectivity and partial agonistic effect in both ␣4␤2 and ␣3␤4 nAChRs (Itier et al, 2004).…”

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confidence: 99%

2-Fluoro-3-(4-nitro-phenyl)deschloroepibatidine Is a Novel Potent Competitive Antagonist of Human Neuronal α4β2 nAChRs

Abdrakhmanova

Damaj²,

Carroll³

et al. 2006

Mol Pharmacol

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A patch-clamp technique in a whole-cell configuration was used to examine the functional activity of recently developed 2-fluoro-3-(substituted phenyl)deschloroepibatidine analogs on two major subtypes of neuronal nicotinic acetylcholine receptors (nAChRs), ␣4␤2 and ␣3␤4, that predominate in the central and peripheral nervous systems, respectively. These epibatidine analogs have been shown previously to possess high binding affinity to ␣4␤2 but not to ␣7 nAChRs and to inhibit nicotine-induced analgesia in behavioral pain tests. The 2-fluoro-3-(4-nitro-phenyl)deschloroepibatidine (4-nitro-PFEB) exhibited the most pronounced antagonist activity among these analogs when tested electrophysiologically on ␣4␤2 nAChRs. It inhibited acetylcholine (ACh)-induced currents in a concentration-dependent manner with an IC 50 value of 0.1 M and produced complete inhibition at ϳ1 M concentration.4-Nitro-PFEB at 0.1 M concentration produced a 4-fold rightward shift in the ACh concentration-response curve without altering maximum ACh-induced response. This inhibitory effect of 4-nitro-PFEB was voltage-and use-independent and was partially reversible at its 1 M concentration. The rise and decay kinetics of ACh-induced currents was not altered in the presence of 4-nitro-PFEB. In contrast to ␣4␤2 nAChRs, this compound did not affect ␣3␤4 nAChR-mediated currents at Յ1 M (IC 50 ϳ63.9 M). Overall, these functional data agree with previous binding and behavioral findings and suggest collectively that 4-nitro-PFEB is the most effective and selective antagonist of ␣4␤2 versus ␣3␤4 and ␣7 nAChRs among the tested analogs, acting on ␣4␤2 nAChR through a competitive mechanism with a potency 17-fold higher than that of dihydro-␤-erythroidine.

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Nicotinic acetylcholine receptors in separate brain regions exhibit different affinities for methyllycaconitine

Cited by 50 publications

References 28 publications

Mecamylamine but not the α7 receptor antagonist α‐bungarotoxin blocks sensitization to the locomotor stimulant effects of nicotine

Mecamylamine but not the α7 receptor antagonist α‐bungarotoxin blocks sensitization to the locomotor stimulant effects of nicotine

Analogs of Methyllycaconitine as Novel Noncompetitive Inhibitors of Nicotinic Receptors: Pharmacological Characterization, Computational Modeling, and Pharmacophore Development

2-Fluoro-3-(4-nitro-phenyl)deschloroepibatidine Is a Novel Potent Competitive Antagonist of Human Neuronal α4β2 nAChRs

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