Synthesis and binding affinity at α4β2 and α7 nicotinic acetylcholine receptors of new analogs of epibatidine and epiboxidine containing the 7-azabicyclo[2.2.1]hept-2-ene ring system.
A group of novel racemic nicotinic ligands structurally related to epibatidine or epiboxidine [(±)-10-(±)-17] was synthesized through a palladium-catalyzed cross-coupling between the appropriate vinyl triflate and a range of organometallic heterocycles. The target compounds were evaluated for binding affinity at the α4β2 and α7 neuronal nicotinic receptors (nAChRs). The set of 3-pyridinyl derivatives (±)-10, (±)-11 and (±)-12 exhibited an affinity for the α4β2 nAChR subtype in the subnanomolar range (K(i) values of 0.20, 0.40 and 0.50nM, respectively) and behaved as α4β2 versus α7 subtype selective ligands. Interestingly, the epiboxidine-related dimethylammonium iodide (±)-17, which retained a good affinity for the α4β2 nAChR (K(i)=13.30nM), tightly bound also to the α7 subtype (K(i)=1.60nM), thus displaying a reversal of the affinity trend among the reference and new nicotinic ligands under investigation.
Dipartimento di Scienze Farmaceutiche 'Pietro Pratesi', Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy. clelia.dallanoce@unimi.it
Clelia
C
Dallanoce
Carlo
C
Matera
Luca
L
Pucci
Cecilia
C
Gotti
Francesco
F
Clementi
Marco De
MD
Amici
Carlo De
CD
Micheli
D001665:Binding Sites / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C525410:7-azabicyclo(2.2.1)heptane; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D011725:Pyridines; D011978:Receptors, Nicotinic; C082748:epibatidine