B. EATON1, O. K. ONAJOLE2,3, L. YU3, H. ZHANG3, J. LIU
1Neurobio., Barrow Neurolog. Inst., Phoenix, AZ; 2Dept. of Biological, Chem. and Physical Sci., Roosevelt Univ., Chicago, IL; 3Dept. of Medicinal Chem. and Pharmacognosy, Univ. of Illinois at Chicago, Chicago, IL; 4Psychogenics, Inc., Tarrytown, NY; 5Lab. of Structural Neurobiology, Dept. of Cell. and Mol. Med., Katholieke Univ. Leuven, Leuven, Belgium; 6Dept. di Scienze Farmaceutiche, Univ. degli Studi di Milano, Milano, Italy; 7of Mol. & Cell. Neurobiology, Ctr. for Neurogenomics and Cognitive Res., VU Univ., Amsterdam, Netherlands; 8Harvard NeuroDiscovery Ctr. and Dept. of Neurol., Brigham and Women’s Hosp., Boston, MA
Depression is among the most common and debilitating symptoms of psychiatric disorders and has thus been the subject of extensive study. Despite the successes so far, currently available drugs have a number of shortcomings including limited efficacy, a need for chronic administration to achieve efficacy, and undesirable side effects from nausea and loss of libido to suicidal ideation and mania. Most research has focused on improving currently available drugs, but gains have been modest. More desirable would be the development of new classes of antidepressants. We have done so via the National Cooperative Drug Discovery/Development Group (NCDDG) Program involving a multidisciplinary research partnership to discover superior agents to treat mental illness. Here we summarize the results of a five year collaboration involving three research groups pursuing the development of novel antidepressant drugs targeting α4β2 nicotinic acetylcholine receptors (nAChR). Using sazetidine-A as a template, medicinal chemists developed multiple series of novel ligands with modifications to the pyridine core, azetidine ring, and alkynyl side chain with the objective of designing α4β2-nAChR partial agonists of high specificity. These ligands were characterized in vitro across an array of nAChR subtypes, and those with the best functional profiles were advanced for behavioral testing, primarily utilizing the SmartCube® assay (Psychogenics, Inc.) and the Forced Swim Test. Isoxazole substitutions of the pyridine core of sazetidine-A produced a few high-affinity compounds, but generally reduced ligand activity and were abandoned. The azetidine ring was successfully replaced with more stable heterocyclic structures of five to seven atoms. Compared to analogs that retained the azetidine ring, compounds with expanded rings trended toward affinities decreased by three to ten-fold. This affinity decrease was impacted by substitutions for the alkynyl group in the distal side chain, with a cyclopropane spacer enabling affinities to be retained. Compounds were generally well tolerated by mice, and a number exhibited antidepressant-like qualities. Side effect and ADME profiles were favorable, but given the high potency of ligands in the in vitro assays, the doses required to achieve in vivo efficacy were surprisingly high. In light of the pharmacokinetics, we believe that in vitro vs in vivo discrepancies in potency are likely due to lower than expected permeability of, or efflux across, the blood brain barrier. Thanks to very high specificity, this higher than expected dose does not appear problematic, and several ligands are suitable candidates for further development.