Chemistry and Pharmacological Characterization of Novel Nitrogen Analogues of AMOP-H-OH (Sazetidine-A, 6-[5-(Azetidin-2-ylmethoxy)pyridin-3-yl]hex-5-yn-1-ol) as α4β2-Nicotinic Acetylcholine Receptor-Selective Partial Agonists

Abstract

In order to advance therapeutic applications of nicotinic ligands, continuing research efforts are being directed toward the identification and characterization of novel nicotinic acetylcholine receptor (nAChR) ligands that are both potent and subtype selective. Herein we report the synthesis and pharmacological evaluation of members of a new series of 3-alkoxy-5-aminopyridine derivatives that display good selectivity for the α4β2-nAChR subtype based on ligand binding and functional evaluations. The most potent ligand in this series, compound 64, showed high radioligand binding affinity and selectivity for rat α4β2-nAChR with a Ki value of 1.2 nM and 4700-fold selectivity for α4β2-over α3β4-nAChR, and ~100-fold selectivity for functional, high-sensitivity, human α4β2-nAChR over α3β4*-nAChR. In the mouse forced swim test, compound 64 exhibited antidepressant-like effects. Structure-activity relationship (SAR) analyses suggest that the introduction of additional substituents to the amino group present on the pyridine ring of the N-demethylated analogue of compound 17 can provide potent α4β2-nAChR-selective ligands for possible use in treatment of neurological and psychiatric disorders including depression.

Effects of sazetidine-A, a selective α4β2* nicotinic receptor desensitizing agent, on body temperature regulation in mice and rats

“…Sazetidine-A has a very high binding affinity for rat α4β2* nicotinic receptors, approximately >10,000-fold and 3,500-fold higher than its affinity at rat α3β4 and rat α7 nicotinic receptors, respectively (Xiao et al, 2006). Consistent with its high selectivity for α4β2* receptors in binding assays, sazetidine-A is a much weaker desensitizer of α3β4 or α7 nicotinic receptor subtypes (Liu et al, 2010; Xiao et al, 2006; Xiao et al, 2008). Thus, sazetidine-A is a highly selective and potent α4β2* nicotinic receptor desensitizer (Xiao et al, 2006).…”

Discovery of Isoxazole Analogues of Sazetidine-A as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists for the Treatment of Depression

“…However, replacement of the acetylene with other functional groups to increase metabolic stability is a logical first choice. 21 Aromatic heterocycles (as in 2 ), for example an isoxazole ring that is present in many bioactive compounds, are potential candidates for this purpose because of their planarity, which adds a minimum of bulk compared to the acetylene group. Several bioactive compounds bearing isoxazole rings have been reported by our group, such as HDAC inhibitors 22 , anti-TB agents 23, 24 , and peroxisome proliferator-activated receptor agonists 25 .…”

Effects of the sazetidine-a family of compounds on the body temperature in wildtype, nicotinic receptor β2−/− and α7−/− mice

“…No hint of an effect was seen in the β2 −/− mice. YL-1-127 was previously shown in our studies (Liu et al, 2010; Xiao et al, 2006; Xiao et al, 2010) to have a potency to desensitize α4β2 nicotinic receptors is 24-fold lower than that of sazetidine-A. As shown in Figure 4, YL-1-127 did not elicit significant hypothermia, at dose up to 3 mg/kg).…”

“…Consistent with its high selectivity for α4β2 receptors in binding assays, sazetidine-A is a much weaker desensitizer of α3β4 or α7 nicotinic receptor subtypes (Liu et al, 2010; Xiao et al, 2006; Xiao et al, 2010). Thus, sazetidine-A is a highly selective and potent α4β2 nicotinic receptor desensitizer (Xiao et al, 2006).…”