Discovery of Highly Potent and Selective α4β2-Nicotinic Acetylcholine Receptor (nAChR) Partial Agonists Containing an Isoxazolylpyridine Ether Scaffold that Demonstrate Antidepressant-like Activity. Part II

Abstract

In our continued efforts to develop α4β2-nicotinic acetylcholine receptor (nAChR) partial agonists as novel antidepressants having a unique mechanism of action, structure activity relationship (SAR) exploration of certain isoxazolylpyridine ethers is presented. In particular, modifications to both the azetidine ring present in the starting structure 4 and its metabolically liable hydroxyl side chain substituent have been explored to improve compound druggability. The pharmacological characterization of all new compounds has been carried out using [3H]epibatidine binding studies together with functional assays based on 86Rb+ ion flux measurements. We found that the deletion of the metabolically liable hydroxyl group or its replacement by a fluoromethyl group not only maintained potency and selectivity, but also resulted in compounds showing antidepressant-like properties in the mouse forced swim test. These isoxazolylpyridine ethers appear to represent promising lead candidates in the design of innovative chemical tools containing reporter groups for imaging purposes and of possible therapeutics.

The potent and selective α4β2*/α6*‐nicotinic acetylcholine receptor partial agonist 2‐[5‐[5‐((S)Azetidin‐2‐ylmethoxy)‐3‐pyridinyl]‐3‐isoxazolyl]ethanol demonstrates antidepressive‐like behavior in animal models and a favorable ADME‐tox profile

“…; Yu et al. ). One newer modification on these techniques involves low temperature incubation before assays to increase the surface expression of high sensitivity (HS) relative to low sensitivity (LS) α 4 β 2 nAChRs and to enhance surface expression of ( α 6/3) β 2 β 3‐nAChRs.…”

“…The in vitro binding affinities of the compounds (LF-3-88, nicotine, and varenicline) are summarized in Table 1. LF-3-88 was found to have potent interactions with b2containing nAChRs (a2b2, a3b2, a4b2, and a4b2*) with The K i values for LF-3-88 are taken from a previous publication (Yu et al 2012).…”

“…Function of nAChR subtypes investigated was established as previously described (Lukas et al 2002;Liu et al 2011;Yu et al 2012). One newer modification on these techniques involves low temperature incubation before assays to increase the surface expression of high sensitivity (HS) relative to low sensitivity (LS) a4b2 nAChRs and to enhance surface expression of (a6/3)b2b3-nAChRs.…”

Recent Developments in Novel Antidepressants Targeting α4β2-Nicotinic Acetylcholine Receptors

“…Replacing the acetylene bond of compound 11 with a substituted cyclopropane or an isoxazole ring lead to compounds 29 and 30 , respectively. 63 , 124 , 125 , 141 Introduction of different amino groups at the 5-position of the pyridine ring yielded a series of 3-alkoxy-5-aminopyridine derivatives exemplified by compound 31 . 123 These compound 11 analogues ( 29 – 31 ) act as α4β2-nAChRs partial agonists (Table 2 ) with low nanomolar binding affinities ( K i = 0.1–1.2 nM) and excellent subtype selectivity at β2*- over β4*-nAChRs (Table 3 ).…”

Phytochemical of Indonesian Macaranga and their Cytotoxic Properties Against P388 Cells

“…Interestingly, β4-containing nAChRs are implicated in nicotine addiction [34,36,39], anxiety-like behavior [44], and in the antidepressant activity of (±)-bupropion [45], (reviewed in [18,46]). Recently published evidence shows that partial agonists and agonists of α4β2 nAChRs present antidepressant activity in animal studies [47,48]. There is evidence showing that subjects with major depressive disorder (MDD) as well as recovered patients have significantly lower β2*-nAChR availability across all brain regions compared with matched healthy subjects [49].…”