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

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 ~ 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.

A Methyl Scan of the Pyrrolidinium Ring of Nicotine Reveals Significant Differences in Its Interactions with α7 and α4β2 Nicotinic Acetylcholine Receptors

“…a A84543 K i 6 S.E.M. binding data of Abreo et al (1996), Ogunjirin et al (2015) reported K i values of 0.15 and 1 nM for A84543 and nicotine, respectively, at rat brain a4b2 receptors.…”

“…The rat brain a4b2 receptor affinity (Table 6) of trans-59-methylA84543 was 7-fold higher than the cis-59-methylA84543. The rat brain high-affinity receptor K i for A84543 has been reported to be 0.15 6 0.01 (Abreo et al, 1996) and 3.44 6 0.40 nM (Ogunjirin et al, 2015), and the a7 receptor K i was reported to be 340 6 50 nM (Ogunjirin et al, 2015). Although the difference we observed between the two methylated A84543 enantiomers was approximately 10Â less than it was for the 59methylnicotines, it is clear that the preferential binding of the trans-59-methylnicotine also applies to trans-59-meth-ylA85443.…”

Site-Selective Switching Strategies to Functionalize Polyazines

“…We next selected a set of biologically active complex polyazines to test the base-switching strategy. An analogue of A-84543, a nicotinic acetylcholine receptor agonist, can be selectively converted into phosphonium ion derivatives on each pyridine ring with complete control of regio- and site-selectivity ( 2o ). The tripyridine system in an MK-1064 precursor is a challenging target for site-selective functionalization.…”