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

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Abstract

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 ~fivefold to tenfold 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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Notes

  1. For nAChRs the *, as per the International Union of Basic and Clinical Pharmacology (IUPHAR), denotes that there may be additional subunits which are presently unknown.

Abbreviations

CTX:

Cerebral cortex

DHβE:

Dihydro-β-erythroidine

[3H]EB:

[3H]epibatidine

FB:

Rat forebrain

nAChRs:

Nicotinic acetylcholine receptors

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Acknowledgments

This work was partially supported by the National Institutes of Health grants 5R24MH067627 and NIGMS-NIH S06 GM08016-34 to MDG.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Howard University, Washington, DC, 20059, USA

    Adebowale E. Ogunjirin, Joseph M. Fortunak & LaVerne L. Brown

  2. Department of Chemistry, Howard University, Washington, DC, 20059, USA

    Joseph M. Fortunak

  3. Department of Pharmacology, Howard University College of Medicine, Washington, DC, 20059, USA

    Martha I. Dávila-García

  4. Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, 20057, USA

    Yingxian Xiao

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  1. Adebowale E. Ogunjirin
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  2. Joseph M. Fortunak
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  5. Martha I. Dávila-García
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Correspondence to Martha I. Dávila-García.

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Special Issue: In honor of Dr. Lynn Wecker.

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Ogunjirin, A.E., Fortunak, J.M., Brown, L.L. et al. Competition, Selectivity and Efficacy of Analogs of A-84543 for Nicotinic Acetylcholine Receptors with Repositioning of Pyridine Nitrogen. Neurochem Res 40, 2131–2142 (2015). https://doi.org/10.1007/s11064-015-1705-z

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