title: Novel diazabicycloalkane delta opioid agonists.
abstract: Here we report the investigation of diazabicycloalkane cores as potential new scaffolds for the development of novel analogues of the previously reported diazatricyclodecane selective delta (δ) opioid agonists, as conformationally constrained homologues of the reference δ agonist (+)-4-[(αR)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of δ opioid agonist prototype 1a with bridged bicyclic cores. 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 3,9-diazabicyclo[4.2.1]nonane, and 3,10-diazabicyclo[4.3.1]decane were adopted as core motifs of the novel derivatives. The compounds were synthesized and biologically assayed as racemic (3-5) or diastereoisomeric (6,7) mixtures. All the novel compounds 3-7 showed δ agonism behaviour and remarkable affinity to δ receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1]octane based compound 4 evidenced improved δ affinity and selectivity relative to SNC80.
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto di Farmacologia Traslazionale, UOS Cagliari, Edificio 5, Località Piscinamanna, 09010 Pula (CA), Italy. Electronic address: giovanni.loriga@ift.cnr.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Loriga
authors.affiliation: Neuroscienze PharmaNess S.c.a r.l., Edificio 5, Località Piscinamanna, 09010 Pula (CA), Italy; KemoTech S.r.l., Edificio 3, Loc. Piscinamanna, 09010 Pula (CA), Italy; Università degli Studi di Sassari, Dipartimento di Chimica e Farmacia, Via F. Muroni 23/A, 07100 Sassari (SS), Italy. Electronic address: paolo.lazzari@kemotech.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Lazzari
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto di Farmacologia Traslazionale, UOS Cagliari, Edificio 5, Località Piscinamanna, 09010 Pula (CA), Italy; Neuroscienze PharmaNess S.c.a r.l., Edificio 5, Località Piscinamanna, 09010 Pula (CA), Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Manca
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto di Farmacologia Traslazionale, UOS Cagliari, Edificio 5, Località Piscinamanna, 09010 Pula (CA), Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Ruiu
authors.affiliation: Consorzio ELPRO, Edificio 5, Località Piscinamanna, 09010 Pula (CA), Italy; Università degli Studi di Cagliari, Dipartimento di Scienze della Vita e dell'Ambiente, Via T. Fiorelli 1, 09126 Cagliari (CA), Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Falzoi
authors.affiliation: Università degli Studi di Sassari, Dipartimento di Chimica e Farmacia, Via F. Muroni 23/A, 07100 Sassari (SS), Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Murineddu
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto di Farmacologia Traslazionale, UOS Cagliari, Edificio 5, Località Piscinamanna, 09010 Pula (CA), Italy; Neuroscienze PharmaNess S.c.a r.l., Edificio 5, Località Piscinamanna, 09010 Pula (CA), Italy.
authors.forename: Mirko Emilio Heiner
authors.initials: ME
authors.lastname: Bottazzi
authors.affiliation: Università degli Studi di Sassari, Dipartimento di Chimica e Farmacia, Via F. Muroni 23/A, 07100 Sassari (SS), Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pinna
authors.affiliation: Università degli Studi di Sassari, Dipartimento di Chimica e Farmacia, Via F. Muroni 23/A, 07100 Sassari (SS), Italy.
authors.forename: Gérard Aimè
authors.initials: GA
authors.lastname: Pinna
mesh_terms: D000473:Alkanes / Q000737:chemistry*; D015394:Molecular Structure; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000473:Alkanes; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu
keywords: Diazabicycloalkane compounds; SNC80 analogues; Structure–activity relationships; δ-Opioid agonist