Synthesis and biological evaluation of novel hybrids of highly potent and selective α4β2-Nicotinic acetylcholine receptor (nAChR) partial agonists

Abstract

We previously reported the cyclopropylpyridine and isoxazolylpyridine ether scaffolds to be versatile building blocks for creating potent α4β2 nicotinic acetylcholine receptor (nAChR) partial agonists with excellent selectivity over the α3β4 subtype. In our continued efforts to develop therapeutic nicotinic ligands, seven novel hybrid compounds were rationally designed, synthesized, and evaluated in [3H]epibatidine binding competition studies. Incorporation of a cyclopropane- or isoxazole-containing side chain onto the 5-position of 1-(pyridin-3-yl)-1,4-diazepane or 2-(pyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane led to highly potent and selective α4β2* nAChR partial agonists with Ki values of 0.5–51.4 nM for α4β2 and negligible affinities for α3β4 and α7. Moreover, compounds 21, 25, and 30 maintained the functional profiles (EC50 and IC50 values of 15–50 nM) of the parent azetidine-containing compounds 3 and 4 in the 86Rb+ ion flux assays. In vivo efficacy of the most promising compound 21 was confirmed in the mouse SmartCube® platform and classical forced swim tests, supporting the potential use of α4β2 partial agonists for treatment of depression.

Synthesis of Novel Nicotinic Ligands with Multimodal Action: Targeting Acetylcholine α4β2, Dopamine and Serotonin Transporters

“…In an related work, Zhang et al [12] described a series of novel ligands containing cyclopropane- or isoxazole- side chains onto the 5-position of 1-(pyridin-3-yl)-1,4-diazepine or 2-(pyridin-3-yl)-2,5-diazabicyclo [2.2.1]heptane which afforded compounds with selective partial agonist propertiers for α4β2* nAChR (K i of 0.5-51.4 nM), displaying also excellent selectivity over the α3β4 subtype. They also found that the most potent compounds, structurally exhibited a pyridine ring connected to a diazepine squeleton, where substituents at the 5-position of the pyridine core were found to be beneficial for the selectivity for α4β2 over α7 and ganglionic nAChRs.…”

“…Graph obtained for the displacement experiments of [ 3 H]-paroxetine for the synthesized compounds [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21] in the cellular background h-SERT induced to 2.5 × 10 −5 M concentration. Fluoxetine (Flx) was used as a control for the compounds under study.…”

“…The α4β2* nAChRs mediate many behaviors related to nicotine addiction and are the primary targets for currently approved smoking cessation agents [9]. However, the success of these strategies must so far be considered limited, as the only α4β2 ligands currently approved for medical use are the partial α4β2 nAChR agonists Varenicline [10], a partial agonist which binds to α4β2 nAChRs with higher affinity but lower efficacy than nicotine, and Cytisine (Figure 1) [11], both of which are used as a smoking cessation aids [12,13]. Varenicline (Figure 1) elicits a moderate and sustained increase of dopamine levels in the brain reward system [14,15], which would elevate low dopamine levels observed during smoking cessation attempts [16].…”

The synthetic and therapeutic expedition of isoxazole and its analogs

“…15) displayed selectivity, as well as excellent antidepressant behavioral activity measured by the mouse forced-swim test. Zhang et al (2016) synthesized some hybrid compounds by combining substituted isoxazolyl side chains with N-pyridyldiamines as selective partial agonists for α4β2-nAChRs. Compound 84 (Fig.…”

“…The chemistry of isoxazoles ( Fig. 1) has been an interesting field of study for decades because of their prominent potential as analgesic (Karthikeyan et al 2009), anti-inflammatory (Rajanarendar et al 2015;Banoglu et al 2016), anticancer (Kumbhare et al 2012;Tzanetou et al 2014), antimicrobial (Siddiqui et al 2013;Basha et al 2015), antiviral ), anticonvulsant (Frølund et al 2007), antidepressant (Yu et al 2012;Zhang et al 2016) and immunosuppressant . The literature survey revealed that the substitution of various groups on the isoxazole ring imparts different activity.…”