In silico approaches for developing sesquiterpene derivatives as antagonists of human nicotinic acetylcholine receptors (nAChRs) for nicotine addiction treatment.

Molecular determinants of the selectivity and potency of α-conotoxin Vc1.1 for human nicotinic acetylcholine receptors

Brain α4β2 nicotinic acetylcholine receptors are involved in the secretion of noradrenaline and adrenaline from adrenal medulla in rats

Here we report the discovery, by high-throughput screening, of three novel (2-amino-5-keto)thiazole compounds that act as selective potentiators of nicotinic acetylcholine receptors. Compound selectivity was assessed at seven human nicotinic acetylcholine receptors (alpha1beta1gammadelta, alpha2beta4, alpha3beta2, alpha3beta4, alpha4beta2, alpha4beta4, and alpha7) expressed in mammalian cells or Xenopus oocytes. At alpha2beta4, alpha4beta2, alpha4beta4, and alpha7, but not alpha1beta1gammadelta, alpha3beta2, or alpha3beta4, submaximal responses to nicotinic agonists were potentiated in a concentration-dependent manner by all compounds. At similar concentrations, no potentiation of 5-hydroxytryptamine, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, GABA(A), and N-methyl-d-aspartate receptors or voltage-gated Na(+) and Ca(2+) channels was observed. Furthermore, these compounds did not inhibit acetylcholine esterase. Further profiling revealed that these compounds enhanced the potency and maximal efficacy of a range of nicotinic agonists at alpha4beta2 nicotinic acetylcholine receptors, a profile typical of allosteric potentiators. At concentrations required for potentiation, the compounds did not displace [(3)H]epibatidine from the agonist-binding site, and potentiation was observed at all agonist concentrations, suggesting a noncompetitive mechanism of action. Blockade of common second messenger systems did not affect potentiation. At concentrations higher then required for potentiation the compounds also displayed intrinsic agonist activity, which was blocked by competitive and noncompetitive nicotinic acetylcholine receptor (nAChR) antagonists. These novel selective nicotinic receptor potentiators should help in clarifying the potential therapeutic utility of selective nAChR modulation for the treatment of central nervous system disorders.

Objective: To investigate the effects of genetic polymorphisms of human nicotinic acetylcholine receptor subunits α3, α4 and α5, which are encoded by CHRNA3, CHRNA4 CHRNA5 genes, respectively, on nicotine addiction and outcomes of pharmacological treatments for smoking cessation. Methods: A total of 143 smokers and 130 non-smokers were included. Genotyping for CHRNA3 rs578776, CHRNA4 rs1044396-rs1044397, CNRNA5 rs16969968 polymorphisms was performed by PCR, flowed by RFLP. Clinical outcomes and success rates of pharmacological treatments for smoking cessation with nicotine replacement therapy (NRT), bupropion or varenicline were determined at the 12th week of the treatment. Results: Overall, 52 out of 143 (36.4%) smokers who received pharmacotherapy were able to quit smoking. Success rates for smoking cessation were similar for female (30.3%) and male (41.6%) subjects (p = 0.16). The success rate for smoking cessation treatment with varenicline (58.5%) was significantly higher as compared to other treatments with NRT (20.0%), bupropion (32.3%) or bupropion + NRT (40.0%) (chi-square test, p = 0.001). Smoker vs. non-smoker status and the clinical outcomes of drugs used for smoking cessation were found similar in subjects carrying wild-type and variant alleles of human nicotinic acetylcholine receptor α subunits. Conclusion: In this study, smoking cessation treatment with varenicline was significantly more effective than treatments with nicotine replacement or bupropion in a cohort of Turkish subjects. Smoker/non-smoker status and the clinical outcomes of treatment with pharmacological agents were similar in subjects with wild-type or variant alleles for human nicotinic acetylcholine receptor subunits α3 (CHRNA3), α4 (CHRNA4) and α5 (CHRNA5).

Many venomous organisms produce toxins that disrupt neuromuscular communication to paralyze their prey. One common class of such toxins comprises nicotinic acetylcholine receptor antagonists (nAChRs). Thus, most toxins that act on nAChRs are targeted to the neuromuscular subtype. The toxin characterized in this report, alpha-conotoxin GIC, is a most striking exception. The 16-amino acid peptide was identified from a genomic DNA clone from Conus geographus. The predicted mature toxin was synthesized, and synthetic toxin was used in all studies described. alpha-Conotoxin GIC shows no paralytic activity in fish or mice. Furthermore, even at concentrations up to 100 microm, the peptide has no detectable effect on the human muscle nicotinic receptor subtype heterologously expressed in Xenopus oocytes. In contrast, the toxin has high affinity (IC(50) approximately 1.1 nm) for the human alpha3beta2 subunit combination, making it the most neuronally selective nicotinic antagonist characterized thus far. Although alpha-conotoxin GIC shares some sequence similarity with alpha-conotoxin MII, which is also a potent alpha3beta2 nicotinic antagonist, it is much less hydrophobic, and the kinetics of channel block are substantially different. It is noteworthy that the nicotinic ligands in C. geographus venom fit an emerging pattern in venomous predators, with one nicotinic antagonist targeted to the muscle subtype (thereby causing paralysis) and a second nicotinic antagonist targeted to the alpha3beta2 nAChR subtype (possibly inhibiting the fight-or-flight response).

Among smokers, approximately half meet criteria for tobacco use disorder, the formal psychiatric diagnosis of addiction to nicotine, making it among the most prevalent of all psychiatric disorders. Minimal contact interventions (MCIs) are intended for a wide variety of healthcare professionals, including psychologists, psychiatrists, primary care physicians, nurses, dentists, and social workers. Formal treatment comes in many forms, but can be broadly defined as being provided by a smoking cessation specialist and having more than one treatment interaction. Nicotine replacement therapy (NRT) provides low doses of nicotine to reduce withdrawal symptoms associated with smoking cessation, weaning the individual away from physiological dependence on nicotine. Bupropion hydrochloride is a nonselective inhibitor of dopamine and norepinephrine transporters and an antagonist of nicotinic acetylcholine receptors. The largest meta-analysis conducted for clinical trials of cytisine found an equal number of serious adverse events in those receiving cytisine and placebo. A number of second-line medications are available for smoking cessation, including clonidine and nortryptiline.

Previous work has shown that quaternization of the pyridine‐N atom of S‐(–)‐nicotine (NIC) affords compounds such as N‐n‐octylnicotinium iodide (NONI) and N‐n‐decylnicotinium iodide (NDNI) that act as competitive nicotinic acetylcholine receptor (nAChR) antagonists at α3β2* and α4β2* subtypes, respectively. To ascertain the rotameric preference about the C3‐C2′ bond of NONI and NDNI for interaction with several nAChR subtypes, two classes of bridged analogs representing extreme rotameric conformations (syn and anti) of NONI and NDNI were synthesized. NIC‐evoked [3H]dopamine ([3H]DA) release from superfused rat striatal slices was used to determine the activity of the analogs at the α3β2* nAChR. [3H]NIC and [3H]methyllycaconitine ([3H]MLA) binding to rat brain membranes were used to determine affinity for α4β2* and α7* nAChRs, respectively. With the exception of BCDD (IC50 value = 1,580 nM), all analogs potently and selectively inhibited NIC‐evoked [3H]DA release (IC50 values = 30–660 nM), indicating antagonism of α3β2* nAChRs. None of the analogs inhibited either [3H]NIC or [3H]MLA binding, indicating a lack of interaction with α4β2* and α7* nAChR subtypes. Interestingly, the C10 N‐alkyl chain analogs, ACD and BCD, had negligible affinity for the α4β2* subtype compared to the high affinity exhibited by NDNI, suggesting that the α4β2* subtype does not recognize the unique stereochemistry of these conformationally restricted analogs. Thus, conformational restriction of N‐n‐alkylnicotinium iodides eliminated inhibitory activity at α4β2* nAChRs, but more importantly afforded high affinity and selectivity for α3β2* nAChRs. Conformational restriction of N‐n‐alkyl analogs of NIC appears to be a viable approach for the development of α3β2*‐selective nAChR antagonists. Drug Dev. Res. 55:172–186, 2002. © 2002 Wiley‐Liss, Inc.

Dequalinium chloride is an antagonists of α7 nicotinic acetylcholine receptors

Nicotinic acetylcholine receptor antagonists for treatment-resistant depression: A meta-analysis

Marine algal pinnatoxins E and F cause neuromuscular block in an in vitro hemidiaphragm preparation

Nefiracetam facilitates hippocampal neurotransmission by a mechanism independent of the piracetam and aniracetam action

Piper betle L. is widely distributed and commonly used medicinally important herb. It can also be used as a medication for type 2 diabetes patients. In this study, compounds of P. betle were screened to investigate the inhibitory action of alpha-amylase and alpha-glucosidase against type 2 diabetes through molecular docking, molecular dynamics simulation, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis. The molecule apigenin-7-O-glucoside showed the highest binding affinity among 123 (one hundred twenty-three) tested compounds. This compound simultaneously bound with the two-target proteins alpha-amylase and alpha-glucosidase, with high molecular mechanics-generalized born surface area (MM/GBSA) values (ΔG Bind = −45.02 kcal mol−1 for alpha-amylase and −38.288 for alpha-glucosidase) compared with control inhibitor acarbose, which had binding affinities of −36.796 kcal mol−1 for alpha-amylase and −29.622 kcal mol−1 for alpha-glucosidase. The apigenin-7-O-glucoside was revealed to be the most stable molecule with the highest binding free energy through molecular dynamics simulation, indicating that it could compete with the inhibitors’ native ligand. Based on ADMET analysis, this phytochemical exhibited a wide range of physicochemical, pharmacokinetic, and drug-like qualities and had no significant side effects, making them prospective drug candidates for type 2 diabetes. Additional in vitro, in vivo, and clinical investigations are needed to determine the precise efficacy of drugs.

Acoustic Startle Response Affected by Aging and Cholinergic Neurotransmitters

36. Conformational flexibility of cyclic imine phycotoxins revealed by long-timescale molecular dynamics simulations

Effects of the plant alkaloid tetrandrine on human nicotinic acetylcholine receptors.