Novel modulators of the dopamine transporter for alcohol and nicotine use disorders

点击翻译按钮获取中文摘要

Abstract Substance use disorders (SUDs) are at epidemic levels in the US [Mack et al 2017] and this has accelerated efforts to find effective pharmacotherapies. All SUDs are associated with increased synaptic dopamine in the mesolimbic pathway. This makes the dopamine transporter (DAT) a primary molecular target, and “atypical” DAT inhibitors, with low abuse potential, are the most promising therapeutic candidates [Reith et al 2015]. Lobinaline, a complex alkaloid from Lobelia cardinalis, is a novel atypical DAT inhibitor [Brown et al 2015], and is a lead for pharmacotherapy of SUDs. However, chemical synthesis of lobinaline is challenging, so the applicants used a proprietary technology to optimize this lead in mutant L. cardinalis plant cells [Brown et al 2016]. This identified two lobinaline N-oxides that are more water soluble than lobinaline, and also modulate the DAT in a different way. Like lobinaline they are competitive inhibitors of the DAT, but paradoxically, and unlike lobinaline, they also increase DA uptake capacity. This unique combination of actions is ideally suited to reversing effects on synaptic DA associated with SUDs without intrinsic reinforcing effects or precipitating withdrawal. Thus, lobinaline and its N-oxides are potential therapeutic agents for all SUDs. However, in addition to activity on the DAT, lobinaline has partial agonist activity at nicotinic receptors [Brown et al 2015], which suggests specific value in nicotine and alcohol use disorders [Rahman et al 2016]. These are currently the most damaging SUDs worldwide [Peacock et al, 2018], and smoking cessation is also the most profitable market in SUD therapeutics. The potential value of lobinaline and the N-oxides in these SUDs was supported by activity in simple animal models, and this phase IIB SBIR proposal is to begin their development as therapeutics. The aims are; (1) to test lobinaline and the N-oxides for “off-target” activity, and to assess their single dose pharmacokinetics and toxicity in rodents, (2) to evaluate them more fully in animal models (including a novel rat model of nicotine plus alcohol self-administration), (3) to scale-up methods for biosynthesis of lobinaline, and its chemical conversion to the N-oxides. The commercial objectives are: (a) to evaluate these novel biosynthetics as potential medications for nicotine and alcohol use disorders, and (b) to leverage this into the commercialization of Naprogenix biotechnology as a plant lead discovery platform. Both objectives will require partnership with a major pharmaceutical or biotechnology company in phase III.