A growing number of literature reports has been focused on ligands targeting neuronal alpha7 nAChRs. In view of application to CNS pathologies, the interest for alpha7 selective agonists/partial agonists is mostly related to deficits in auditory sensory processing, which have been hypothesized to lead to a state of sensory overload and contribute to attentional and cognitive dysfunctions in various CNS diseases, among them schizophrenia. Moreover, agonist at this subtype, alone or co-administered with antipsychotic drugs, showed in vivo efficacy in preclinical models predictive of cognitive-enhancing and antipsychotic-like activities. Furthermore, selective agonists of alpha7 nAChRs are emerging as promising lead candidates for the treatment of inflammatory diseases. In the search for novel promising alpha7 nAChR agonists, the rigid quinuclidine scaffold and those of similar bicyclic tertiary bases represent first choice core-fragments for the selective molecular recognition of ligands by the alpha7 channel protein, as exemplified by AR-R17779. As part of an ongoing research project aimed at identifying new heterocyclic derivatives targeting neuronal nAChRs, we characterized some racemic spirocyclic quinuclidinyl-delta2-isoxazolines, represented by compounds 1, as selective alpha7 vs alpha4beta2 nicotinic agonists/partial agonists. We now report the synthesis and the affinity profile at alpha7 and alpha4beta2 nAChRs of the two sets of derivatives 2 and 3, in which the quinuclidine basic fragment of the parent derivatives has been replaced by the 1-azabicyclo[2.2.1]heptane and the 1-methylpiperidine moieties, respectively. The permanently charged methyl iodides of the tertiary bases 2 and 3 were also prepared and assayed for their binding affinity at the two neuronal nAChR subtypes.

Novel spirocyclic delta2-isoxazoline derivatives as lower homologues of selective agonists for neuronal alpha-7 nicotinic acetylcholine receptor subtypes / C. Dallanoce, F. Frigerio, C. Matera, F. Gritti, C. Gotti, L. Pucci, F. Clementi, C. De Micheli - In: Proceedings of XX National Meeting on Medicinal Chemistry[s.l] : Società Chimica Italiana, 2010. - pp. 93-93 (( Intervento presentato al 20. convegno National Meeting on Medicinal Chemistry tenutosi a Abano Terme nel 2010.

Novel spirocyclic delta2-isoxazoline derivatives as lower homologues of selective agonists for neuronal alpha-7 nicotinic acetylcholine receptor subtypes

C. Dallanoce
Primo
;
F. Frigerio
Secondo
;
C. Matera;F. Clementi
Penultimo
;
C. De Micheli
Ultimo
2010

Abstract

A growing number of literature reports has been focused on ligands targeting neuronal alpha7 nAChRs. In view of application to CNS pathologies, the interest for alpha7 selective agonists/partial agonists is mostly related to deficits in auditory sensory processing, which have been hypothesized to lead to a state of sensory overload and contribute to attentional and cognitive dysfunctions in various CNS diseases, among them schizophrenia. Moreover, agonist at this subtype, alone or co-administered with antipsychotic drugs, showed in vivo efficacy in preclinical models predictive of cognitive-enhancing and antipsychotic-like activities. Furthermore, selective agonists of alpha7 nAChRs are emerging as promising lead candidates for the treatment of inflammatory diseases. In the search for novel promising alpha7 nAChR agonists, the rigid quinuclidine scaffold and those of similar bicyclic tertiary bases represent first choice core-fragments for the selective molecular recognition of ligands by the alpha7 channel protein, as exemplified by AR-R17779. As part of an ongoing research project aimed at identifying new heterocyclic derivatives targeting neuronal nAChRs, we characterized some racemic spirocyclic quinuclidinyl-delta2-isoxazolines, represented by compounds 1, as selective alpha7 vs alpha4beta2 nicotinic agonists/partial agonists. We now report the synthesis and the affinity profile at alpha7 and alpha4beta2 nAChRs of the two sets of derivatives 2 and 3, in which the quinuclidine basic fragment of the parent derivatives has been replaced by the 1-azabicyclo[2.2.1]heptane and the 1-methylpiperidine moieties, respectively. The permanently charged methyl iodides of the tertiary bases 2 and 3 were also prepared and assayed for their binding affinity at the two neuronal nAChR subtypes.
nicotinic receptors; alpha-7; nAChRs; ACh; acetylcholine; cholinergic; nicotinic agonists; spirocyclic compounds
Settore CHIM/08 - Chimica Farmaceutica
Società Chimica Italiana
Book Part (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/151340
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