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 (delta) opioid agonists, as conformationally constrained homologues of the reference delta agonist (+)-4-[(alpha R)-alpha((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of d 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 d agonism behaviour and remarkable affinity to d receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1] octane based compound 4 evidenced improved d affinity and selectivity relative to SNC80.

Novel diazabicycloalkane delta opioid agonists

FALZOI, MATTEO;
2015

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 (delta) opioid agonists, as conformationally constrained homologues of the reference delta agonist (+)-4-[(alpha R)-alpha((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of d 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 d agonism behaviour and remarkable affinity to d receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1] octane based compound 4 evidenced improved d affinity and selectivity relative to SNC80.
Delta-Opioid agonist; SNC80 analogues; Diazabicycloalkane compounds; Structure-activity relationships
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11584/116973
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