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Bioorg Med Chem. 2015 Sep 1;23(17):5527-38. doi: 10.1016/j.bmc.2015.07.036. Epub 2015 Jul 27.

Novel diazabicycloalkane delta opioid agonists.

Author information

1
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.
2
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.
3
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.
4
Consiglio Nazionale delle Ricerche, Istituto di Farmacologia Traslazionale, UOS Cagliari, Edificio 5, Località Piscinamanna, 09010 Pula (CA), Italy.
5
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.
6
Università degli Studi di Sassari, Dipartimento di Chimica e Farmacia, Via F. Muroni 23/A, 07100 Sassari (SS), Italy.

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.

KEYWORDS:

Diazabicycloalkane compounds; SNC80 analogues; Structure–activity relationships; δ-Opioid agonist

PMID:
26252963
DOI:
10.1016/j.bmc.2015.07.036
[Indexed for MEDLINE]

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