Differential Modulation of Brain Nicotinic Acetylcholine Receptor Function by Cytisine, Varenicline, and Two Novel Bispidine Compounds: Emergent Properties of a Hybrid Molecule

Abstract

Partial agonist therapies for the treatment of nicotine addiction and dependence depend on both agonistic and antagonistic effects of the ligands, and side effects associated with other nAChRs greatly limit the efficacy of nicotinic partial agonists. We evaluated the in vitro pharmacological properties of four partial agonists, two current smoking cessation drugs, varenicline and cytisine, and two novel bispidine compounds, BPC and BMSP, by using defined nAChR subtypes expressed in Xenopus laevis oocytes and human embryonic kidney 293 cells. Similar to varenicline and cytisine, BPC and BMSP are partial agonists of a4b2 nAChRs, although BMSP produced very little activation of these receptors. Unlike varenicline and cytisine, BPC and BMSP showed desired low activity. BPC produced mecamylaminesensitive steady-state activation of a4* receptors that was not evident with BMSP. We evaluated the modulation of a4*-and a7-mediated responses in rat lateral geniculate nucleus (LGN) neurons and hippocampal stratum radiatum (SR) interneurons, respectively. The LGN neurons were sensitive to a very low concentration of varenicline, and the SR interneuron responses were also sensitive to varenicline at a submicromolar concentration. Although 300 nM BPC strongly inhibited the AChevoked responses of LGN neurons, it did not inhibit the a7 currents of SR interneurons. Similar results were observed with 300 nM BMSP. Additionally, the bispidine compounds were efficacious in the mouse tail suspension test, demonstrating that they affect receptors in the brain when delivered systemically. Our data indicate that BPC and BMSP are promising a4b2* partial agonists for pharmacotherapeutics.

The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: Carboxamide derivatives with different spacer motifs

“…Compound 35 was further evaluated and recently discovered as an in vivo active, highly selective agent with antidepressive effect in a mouse model. 26 Compound 15 was the most potent agonist at α3β4* in this compound series. No strong effects were observed for α7 subtype.…”

The twin drug approach for novel nicotinic acetylcholine receptor ligands

“…Our “twin” compound 17a (BPC) shows superior subtype selectivity and functionality in comparison with the smoking cessation drugs cytisine and varenicline, and the efficacy in the mouse tail suspension test underlines its potential use in mood disorders. 22 Previous studies have shown that larger diaza(bi)cyclic systems providing the protonated nitrogen have higher affinity for α4β2* nAChR due to lipophilic interactions. 7,28 The piperazine derivative 20a displays the lowest affinity among the three compounds, which is about 770-fold lower in comparison with compound 17a .…”

“…3A). 22 BPC 17a is a “non-identical twin drug” using the overlap mode in its design (Fig. 3) and has partial agonist activity for α4β2* nAChRs, improved selectivity profiles over varenicline and cytisine, and efficacy in the mouse tail suspension test.…”

“…3) and has partial agonist activity for α4β2* nAChRs, improved selectivity profiles over varenicline and cytisine, and efficacy in the mouse tail suspension test. 22 The design strategy for BPC 17a has not been developed previously for α4β2* nAChR ligands, especially using the hydrogen bond acceptor (HBA) moiety for the overlap mode. Here, we report on the design, synthesis, and in vitro evaluation of “twin” compounds based on the “overlap” mode as pharmacological tools and as new lead compounds for β2-containing nAChRs.…”

The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor (nAChR) ligands. Part 1: The influence of different hydrogen bond acceptor systems on alkyl and (hetero)aryl substituents

“…Both studies were the foundation for the development of in vivo active compounds recently published. 62 …”