New spirocyclic Δ2-isoxazoline derivatives related to selective agonists of α7 neuronal nicotinic acetylcholine receptors

Identification of α7 Nicotinic Acetylcholine Receptor Silent Agonists Based on the Spirocyclic Quinuclidine‐Δ2‐Isoxazoline Scaffold: Synthesis and Electrophysiological Evaluation

“…The presence in the structure of a positive ammonium head, which has been proposed as a crucial requirement to induce α7 silent agonism, prompted us to evaluate this panel of spirocyclic Δ 2 ‐isoxazoline derivatives for their silent activity. As reported in Table , the quinuclidinyl 3‐benzyloxy‐Δ 2 ‐isoxazoline 11 and the N , N ‐dimethylpiperidinyl 3‐bromo‐ and 3‐methoxy‐Δ 2 ‐isoxazolines 14 and 15 were identified as silent agonists. The latter are defined as those compounds that are unable to or very weakly activate channel opening when used alone but that produce channel activation in the presence of PAMs by inducing PAM‐sensitive desensitization of the receptor.…”

“…Compounds 6 – 16 (Table ) behaved as low‐affinity α7 nicotinic ligands, with inhibition constant values ( K i , against [ 125 I]α‐bungarotoxin) in the range of 0.1–13 μ m . The presence in the structure of a positive ammonium head, which has been proposed as a crucial requirement to induce α7 silent agonism, prompted us to evaluate this panel of spirocyclic Δ 2 ‐isoxazoline derivatives for their silent activity.…”

“…Compounds 6 – 16 assayed in this study and intermediates 25 – 27 were synthesized according to published procedures …”

“…However,t he structure-activity relationships( SARs) of silent agonists are still poorly defined, and in this study,w e expand the chemical space of putative silent compounds and aim to provide furtheri nsight into their molecular interactions with the a7n AChR. To this end, we first explored the series of knownq uaternary ammonium compounds 6-16 [25,26] for their a7n AChRs ilent-agonist activity (Table 1);t hese compounds were chosen from an array of selective nicotinic agonists studied by our research group. [25][26][27][28][29][30][31][32][33][34] Among the screened compounds, 11, 14,a nd 15 ( Figure 2) turned out to behave as 1,N S-6740 [16] 0.06 AE 0.02 [b] 118 AE 22 [d] 2,K C-1 [20] 0.083 AE 0.009 [b] 17.8 AE 2.4 [d] 3,d iEPP [22,23] 0.002 AE 0.003 1.3 AE 0.3 4,TFM-diEPP [23] 0.…”

Determination of Acid Dissociation Constants of Poorly Water-Soluble Nicotinic Ligands by Means of Electrophoretic and Potentiometric Techniques

“…As part of an ongoing research program on the study of novel heterocyclic derivatives targeting nAChR subtypes [7][8][9][10], we designed and prepared the set of compounds 2-9, in which the ∆ 2 -isoxazoline moiety of reference ligand 1 was replaced by the 1,2,3-triazole ring ( Figure 1). Along with their pharmacodynamic profile, ligands of putative pharmacological significance must be investigated also for their physicochemical features such as solubility, lipophilicity, hydrogen bonding capacity and charge, which affect their in vivo pharmacokinetic behaviour.…”