Thediazabicyclic molecule bispidine named by the chemist Carl Mannich in 1930, is a naturally occurring scaffold with interesting features. Bispidine can form different conformers, has high basicity, can attack dichloromethane, has metal ion coordination properties and interacts with nicotinic acetylcholine receptors. In this review we will discuss important properties, synthetic pathways and biological activities of bispidine and some derivatives. Bispidine can function as a scaffold for compounds with very diverse biological activities, e.g. interacting with ion channels, G-protein coupled receptors, and enzymes, and is even used for the development of new in vivo radiotracers.

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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.