A-85380 [3-(2(S)-azetidinylmethoxy) pyridine]: In Vitro pharmacological properties of a novel, high affinity α4β2 nicotinic acetylcholine receptor ligand

Sullivan, James P.; Donnelly‐Roberts, Diana L.; Briggs, Clark A.; Anderson, David J.; Gopalakrishnan, Murali; Piattoni-Kaplan, Marietta; Campbell, John R.; McKenna, David G.; Molinari, Edwardo; Hettinger, Ann-Marie; Garvey, David S.; Wasicak, James T.; Holladay, Mark W.; Williams, Michael; Arnerić, Stephen P.

doi:10.1016/0028-3908(96)84644-2

Cited by 122 publications

(54 citation statements)

References 23 publications

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“…These include ABT-418, ABT-089, ABT-594, SIB-1765F, SIB-1508Y, RJR-2403, GTS-21 or DMXB, SIB-1663, A-85380, and epibatidine ( Fig. 10) (Anderson et al, 1995;Bencherif et al, 1996;Cosford et al, 1996;Davila-Garcia et al, 1997;Holladay et al, 1997;Menzaghi et al, 1997;Sullivan et al, 1997;Bannon et al, 1998;Vernier et al, 1998;Khan et al, 2001). Most of these compounds have similarities in either the pyridine or pyrrolidine ring to nicotine and might be expected to undergo some of the same metabolic reactions.…”

Section: Pharmacokinetics and Metabolism Of Nicotine Analogsmentioning

confidence: 99%

Metabolism and Disposition Kinetics of Nicotine

2005

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Section: Pharmacokinetics and Metabolism Of Nicotine Analogsmentioning

confidence: 99%

Metabolism and Disposition Kinetics of Nicotine

2005

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“…Its increased affinity for 4 2 receptors, found at a high density in the mammalian CNS, is interesting because it would allow for a selective non-opioid analgesic agent [47], however its clinical use is not acceptable due to its toxicity [52]. Nevertheless, the ongoing search for less toxic synthetic derivatives would be advantageous especially with regards to reducing the consumption of live frogs [53].…”

Section: Epibatidinementioning

confidence: 99%

Historical and Current Perspectives of Neuroactive Compounds Derived from Latin America

Aguayo

Guzmán²,

Pérez³

et al. 2006

MRMC

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Plants and invertebrates in Latin America have contributed to a great extent in the use, discovery and development of novel neuroactive tools. Significantly, these neuroactive drugs have proven to be particularly important for our current understanding of the physiology and pharmacology of the nervous system. In addition, these discoveries have helped to build the modern and successful pharmacological business that we know today. For example, curare helped to introduce the use of muscle relaxing agents into modern surgical techniques. The discovery of cocaine from the leaves of Peruvian coca plants was instrumental in the discovery of local anesthetics. The search and discovery for useful neuroactive compounds derived from Latin America has also been ongoing in other areas and new applications for quinine, capsaicin and epibatidine were recently described. Besides these organic compounds, several peptides produced by spiders and other invertebrates to hunt their prey also induce effects in channels and membrane receptors at very low concentrations, indicating their high potency and selectivity. It is likely that new pharmaceutics will be developed from these molecules. The interest to renew the search for new compounds is timely, since largely unexplored lands, such as the Amazon and Patagonia, hold an important number of plants and animals that contain exciting new active compounds. With the introduction of new techniques to isolate, identify and characterize the molecular targets and actions of chemical entities, together with the need for more potent and selective compounds to treat neurological conditions, it is necessary to broaden the current exploratory effort in order to find more beneficial uses.

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“…This close homology has hindered detailed characterization of their individual functional roles and has made it difficult to design nAChR subtype-specific ligands for use as therapeutic agents. One positive outcome of these studies has been the development of ligands for the β2-containing nAChRs, the most abundant in the CNS [17], has been the least challenging and therefore has received the most attention, partly because, with very few exceptions, old and new nicotinic ligands show highest affinity [18–23] and/or higher selectivity for these receptors [2,22–28]. It should be emphasized here, however, that selectivity of all nicotinic drugs so far studied is at best relative, and highly dependent on concentration [24,25,28].…”

Section: Introductionmentioning

confidence: 99%

“…According to a pre-existing pharmacophore model for nicotine, initially proposed by Beers and Reich (1970) [29] and later modified by others [30], compounds will fit the nAChRs orthosteric site if they meet certain criteria. Thus, minor structural modifications on nicotine has yielded a number of useful ligands including A-85380 [23], A-84543 [22], sazetidine-A [34] and many of their analogues [22,23,31–33], which, although not fully selective, have diverse affinities and high affinity ratios for different nAChR subtypes [22–28,31–33, for review see 2,9], unfortunately, most have not been as successful in the clinic [2,4]. …”

Section: Introductionmentioning

confidence: 99%

Competition, Selectivity and Efficacy of Analogs of A-84543 for Nicotinic Acetylcholine Receptors with Repositioning of Pyridine Nitrogen

et al. 2015

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Nicotinic acetylcholine receptors (nAChRs) play a crucial role in a number of clinically relevant mental and neurological pathways, as well as autonomic and immune functions. The development of subtype-selective ligands for nAChRs therefore is potentially useful for targeted therapeutic management of conditions where nAChRs are involved. We tested if selectivity for a particular nAChR subtype can be achieved through small structural modifications of a lead compound containing the nicotinic pharmacophore by changing the distance between the electronegative elements. For this purpose, analogs of A-84543 were designed, synthesized and characterized as potentially new nAChR subtype-selective ligands. Compounds were tested for their binding properties in rat cerebral cortical tissue homogenates, and subtype-selectivity was determined using stably transfected HEK cells expressing different nAChR subtypes. All compounds synthesized were found to competitively displace [3H]-epibatidine ([3H]EB) from the nAChR binding site. Of all the analogues, H-11MNH showed highest affinity for nAChRs compared to a ~ 5 to10-fold lower affinity of A-84543. All other compounds had affinities > 10,000 nM. Both A-84543 and H-11MNH have highest affinity for α2β2 and α4β2 nAChRs and show moderate affinity for β4- and α7-containing receptors. H-11MNH was found to be a full agonist with high potency at α3β4, while A-84543 is a partial agonist with low potency. Based on their unique pharmacological binding properties we suggest that A-84543 and its desmethylpyrrolidine analog can be useful as pharmacological ligands for studying nAChRs if selective pharmacological and/or genetic tools are used to mask the function of other receptors subtypes.

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A-85380 [3-(2(S)-azetidinylmethoxy) pyridine]: In Vitro pharmacological properties of a novel, high affinity α4β2 nicotinic acetylcholine receptor ligand

Cited by 122 publications

References 23 publications

Metabolism and Disposition Kinetics of Nicotine

Metabolism and Disposition Kinetics of Nicotine

Historical and Current Perspectives of Neuroactive Compounds Derived from Latin America

Competition, Selectivity and Efficacy of Analogs of A-84543 for Nicotinic Acetylcholine Receptors with Repositioning of Pyridine Nitrogen

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