Competition, Selectivity and Efficacy of Analogs of A-84543 for Nicotinic Acetylcholine Receptors with Repositioning of Pyridine Nitrogen.
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 [(3)H]-epibatidine ([(3)H]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.
Department of Pharmaceutical Sciences, Howard University, Washington, DC, 20059, USA.
Adebowale E
AE
Ogunjirin
Department of Pharmaceutical Sciences, Howard University, Washington, DC, 20059, USA.|Department of Chemistry, Howard University, Washington, DC, 20059, USA.
Joseph M
JM
Fortunak
Department of Pharmaceutical Sciences, Howard University, Washington, DC, 20059, USA.
LaVerne L
LL
Brown
Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, 20057, USA.
Yingxian
Y
Xiao
Department of Pharmacology, Howard University College of Medicine, Washington, DC, 20059, USA. mdavila-garcia@howard.edu.
Martha I
MI
Dávila-García
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D009584:Nitrogen / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
C116733:3-(2-(pyrrolidinyl)methoxy)pyridine; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011725:Pyridines; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; D009538:Nicotine; C082748:epibatidine; D009584:Nitrogen; C023666:pyridine
A-85380; Cerebral cortex; Epibatidine; H-11MNH; Nicotine; Saturation