The goal of the proposed Phase II SBIR is to advance a novel class of alpha3beta4 nicotinic acetylcholine receptor antagonists (new molecular entities), which show excellent in vivo efficacy in blocking nicotine self- administratio and reinstatement of nicotine seeking, towards development as smoking cessation therapy. We have discovered a series of highly potent alpha3beta4 nAChR functional antagonists, all of which have single-digit nanomolar binding affinity and >100-fold target selectivity versus the closely related 42 and 7 nAChR subtypes. In our successful Phase I effort, we showed that three lead compounds from this series not only significantly block nicotine self-administration in rats, at low doses, without effect on food responding, but also block reinstatement of nicotine seeking, an animal model of relapse. The significant efficacy of these selective alpha3beta4 nAChR ligands strongly suggests that alpha3beta4 nAChR functional antagonism'is a promising pharmacological mechanism for smoking cessation pharmacotherapy. We have achieved all of the Aims of our Phase I SBIR and conducted additional studies to support the suitability of this class of compounds for further drug development. We now seek Phase II support to advance an optimized set of lead candidates, through a series of 'de-risking'experiments, with the goal of selecting a 'development candidate'for the proposed indication (smoking cessation). A second goal is to position at least one other compound in our series as backup for the same indication or as a future development candidate for other indications.
In Aim 1, we will scale-up (non-GMP) a panel of optimized alpha3beta4 nAChR ligands for preformulation and development activities.
In Aim 2, the development candidates will be characterized in a series of ADME studies and PK in two species.
In Aim 3, confirmation of oral efficacy of the selected candidates will be determined in a rat model of nicotine self-administration and reinstatement of nicotine-seeking.
In Aim 4, we will carry out detailed safety pharmacology and early toxicology studies including GLP cardiovascular safety for dog, functional observational battery and Range-finding toxicology in two species. The desired outcome of this project will be the selection of the most suitable 'development candidate', which will be immediately ready for definitive GLP toxicology studies for an IND submission and advancement as smoking cessation pharmacotherapy.
The overall goal of the proposed research is to advance the development of novel smoking cessation medications. This project is of high significance because these potent lead compounds are targeted to a subtype of the nicotinic receptors that have been genetically associated with increased smoking behavior and inability to quit. These new drug candidates have shown superior efficacy in inhibiting nicotine self- administration and relapse in animal models, attesting to the genetic association studies that this nicotinic receptor subtype indeed plays a role in addiction to nicotine. These drug candidates represent a new approach for smoking cessation aids, that are urgently needed, given that the current repertoire of cessation aids are besieged with black box warnings. We seek to continue the development of this novel class of drug candidates into safe and effective medications for smoking cessation and maintaining abstinence.
|Yuan, Menglu; Malagon, Ariana M; Yasuda, Dennis et al. (2017) The ?3?4 nAChR partial agonist AT-1001 attenuates stress-induced reinstatement of nicotine seeking in a rat model of relapse and induces minimal withdrawal in dependent rats. Behav Brain Res 333:251-257|
|Cippitelli, Andrea; Wu, Jinhua; Gaiolini, Kelly A et al. (2015) AT-1001: a high-affinity ?3?4 nAChR ligand with novel nicotine-suppressive pharmacology. Br J Pharmacol 172:1834-45|
|Cippitelli, Andrea; Brunori, Gloria; Gaiolini, Kelly A et al. (2015) Pharmacological stress is required for the anti-alcohol effect of the ?3?4* nAChR partial agonist AT-1001. Neuropharmacology 93:229-36|
|Khroyan, Taline V; Yasuda, Dennis; Toll, Lawrence et al. (2015) High affinity ?3?4 nicotinic acetylcholine receptor ligands AT-1001 and AT-1012 attenuate cocaine-induced conditioned place preference and behavioral sensitization in mice. Biochem Pharmacol 97:531-541|
|Zaveri, Nurulain T; Bertrand, Sonia; Yasuda, Dennis et al. (2015) Functional characterization of AT-1001, an ?3?4 nicotinic acetylcholine receptor ligand, at human ?3?4 and ?4?2 nAChR. Nicotine Tob Res 17:361-7|
|Costello, Matthew R; Reynaga, Daisy D; Mojica, Celina Y et al. (2014) Comparison of the reinforcing properties of nicotine and cigarette smoke extract in rats. Neuropsychopharmacology 39:1843-51|
|Wu, Jinhua; Perry, David C; Bupp, James E et al. (2014) [¹²?I]AT-1012, a new high affinity radioligand for the ?3?4 nicotinic acetylcholine receptors. Neuropharmacology 77:193-9|
|Muldoon, P P; Jackson, K J; Perez, E et al. (2014) The ?3?4* nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies. Br J Pharmacol 171:3845-57|