Our initial grant application proposed "to synthesize and evaluate novel CBI ligands for the treatment of addiction to methamphetamine (METH)." The overall research goal was to ""identify CBI antagonists and CBI agonists with low in vivo efficacy" and included design and synthesis of: 1) novel CBI antagonists with neutral or inverse agonist efficacy including biarylpyrazole and biarylimidazole analogs;and 2) CBI ligands varying in agonist efficacy including i) aminoalkylindole (AAI) ligands based on our CBI agonist prototype AM5983 and ii) biarylether sulfonate (BAS) analogs based on the partial agonist BAY59-3074. To date, we have fulfilled the goals of our initial proposal including synthesis and evaluation of novel CBI ligands from the specified chemical classes as well as in vitro and in vivo evaluation of the most promising compounds. This work has led to the discovery of a new family of CBI neutral antagonists as well as CBI agonists with different efficacies. In the search for "druggable" CBI partial agonists we also have expanded our scope to include two novel classes of cannabinergic ligands that provided us with promising initial results. During the next five year period we intend to advance our current work so as to move our advanced candidate medications for stimulant addiction into the preclinical pre-IND stage. It is important to note that our successful pre-IND candidate and backup compounds also will be eligible for testing as potentially useful medications for nicotine, as well as methamphetamine, addiction. To accomplish our goals, we will design, synthesize, and characterize later generation neutral CBI antagonists with improved overall pharmacological profiles as potential back-ups for our current class of CBI neutral antagonists. The major effort of optimization will be towards obtaining efficacious and safe IND candidates. This will encompass both pyrazole and imidazole analogs with good brain penetration and enhanced oral bioavailability. We also will develop novel CBI selective agonists with low agonist efficacy. We will continue to optimize the two currently-studied classes of CBI agonists (AAI, BAS) for CB1/CB2 selectivity, low CBI efficacy and druggability profiles and, as well, extend the available SAR to identify druggable candidates from two additional cannabinergic classes (adamantyl cannabinoids and (+)-cannabidiol analogswith absolute stereochemistry opposite of the naturally occurring (-)-cannabidiol. The most promising compounds from these synthesis programs will be further studied to determine their a) in vitro elTicacy and b) relative ability to cross the blood brain barrier. Based on these data, novel ligands will be selected for in vivo studies to determine a) behavioral profiles of action using CBI-mediated hypothermia and operant assays especially designed to identify low-efficacy agonists in rats and monkeys and, for the most advantageous candidates, b) attenuation of methamphetamine's relapse-related effects using drug discrimination and i.v. selfadministration procedures in monkeys.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DA023142-07
Application #
8473835
Study Section
Special Emphasis Panel (NSS)
Program Officer
Shih, Ming L
Project Start
2007-05-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
7
Fiscal Year
2013
Total Cost
$687,900
Indirect Cost
$165,746
Name
Northeastern University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
Kangas, Brian D; Bergman, Jack (2014) Repeated acquisition and discrimination reversal in the squirrel monkey (Saimiri sciureus). Anim Cogn 17:221-8
Jarbe, Torbjorn U C; LeMay, Brian J; Halikhedkar, Aneetha et al. (2014) Differentiation between low- and high-efficacy CB1 receptor agonists using a drug discrimination protocol for rats. Psychopharmacology (Berl) 231:489-500
Sharma, Rishi; Nikas, Spyros P; Guo, Jason Jianxin et al. (2014) C-ring cannabinoid lactones: a novel cannabinergic chemotype. ACS Med Chem Lett 5:400-4
Justinova, Zuzana; Mascia, Paola; Wu, Hui-Qiu et al. (2013) Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid. Nat Neurosci 16:1652-61
Kangas, Brian D; Delatte, Marcus S; Vemuri, V Kiran et al. (2013) Cannabinoid discrimination and antagonism by CB(1) neutral and inverse agonist antagonists. J Pharmacol Exp Ther 344:561-7
Teng, Heidi; Thakur, Ganesh A; Makriyannis, Alexandros (2011) Conformationally constrained analogs of BAY 59-3074 as novel cannabinoid receptor ligands. Bioorg Med Chem Lett 21:5999-6002
Storr, M A; Bashashati, M; Hirota, C et al. (2010) Differential effects of CB(1) neutral antagonists and inverse agonists on gastrointestinal motility in mice. Neurogastroenterol Motil 22:787-96, e223
Cluny, N L; Vemuri, V K; Chambers, A P et al. (2010) A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents. Br J Pharmacol 161:629-42
Järbe, Torbjörn U C; Gifford, Roger S; Makriyannis, Alexandros (2010) Antagonism of ??-THC induced behavioral effects by rimonabant: time course studies in rats. Eur J Pharmacol 648:133-8