title: Design of novel 3,6-diazabicyclo[3.1.1]heptane derivatives with potent and selective affinities for α4β2 neuronal nicotinic acetylcholine receptors.
abstract: New analogues (3a-l) of the previously described α4β2 selective ligand 3-(6-halopyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptanes (2a,b) have been synthesized and their binding activity for neuronal acetylcholine receptor subtypes α4β2 and α7 were assayed. Six of these compounds (3a,b,c,j,k and l) showed high affinity and selectivity for α4β2 receptors. The phenylpyridyl-diazabicycloheptane 3c displayed Ki value of 11.17 pM for α4β2, in line with that of the halogenated homologues 3a,b, although it was characterized by an improved selectivity (Ki = 17 μM for α7 receptors). The influence of substitutions on the phenylpyridyl moiety on binding at both α4β2 and α7 receptors has been examined through the Topliss decision tree analysis. Substitution with electron-donating groups (as CH3 and OCH3) resulted in a good affinity for α4β2 receptors and substantially no affinity for α7. Amongst all the tested phenyl-substituted compounds, the p-NO2-phenyl substituted analogue 3j exhibited the highest α4β2 affinity, with Ki value comparable to that of 3c. Intrinsic α4β2 receptor mediated activity in [(3)H]-DA release assay was showed by compound 3a as well as by the reference analogue 2a, whereas phenyl substituted derivative 3c exhibited α4β2 antagonist activity.
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Deligia
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Deiana
authors.affiliation: CNR, Neuroscience Institute-Milano, Biometra Institute University of Milan, Milan, Via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gotti
authors.affiliation: KemoTech Srl, Building 3, Loc. Piscinamanna, 09010 Pula, CA, Italy; PharmaNess Scarl, Building 5, Loc. Piscinamanna, 09010 Pula, CA, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Lazzari
authors.affiliation: PharmaNess Scarl, Building 5, Loc. Piscinamanna, 09010 Pula, CA, Italy.
authors.forename: Mirko E H
authors.initials: ME
authors.lastname: Bottazzi
authors.affiliation: CNR, Neuroscience Institute-Milano, Biometra Institute University of Milan, Milan, Via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Pucci
authors.affiliation: CNR, Neuroscience Institute-Milano, Biometra Institute University of Milan, Milan, Via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fasoli
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Ragusa
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Pinna
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy. Electronic address: muri@uniss.it.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Murineddu
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D053961:Azabicyclo Compounds; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2
keywords: 3,6-diazabicyclo[3.1.1]heptanes; Agonism; Antagonism; Synthesis; α(4)β(2) neuronal nicotinic acetylcholine receptors selectivity