Nanotechnology-based drug delivery systems for enhancing bioavailability and reducing brain penetration of novel cannabinoid-1 receptor (CB1R) inverse agonists

Introduction: During the last few decades, there has been an epidemic increase in the worldwide prevalence of obesity and its metabolic complications. Currently, there is no available medication that simultaneously targets all of the metabolic consequences of obesity, justifying the search for novel approaches. Cannabinoid 1 receptor (CB1R) antagonists reduce body weight and improve the associated hormonal/metabolic abnormalities in obese rodents and humans. However, their values as anti-obesity agents are limited by side effects mediated at CB1R in the CNS. CB1R and endocannabinoids are also present in peripheral tissues, and several lines of evidence suggest that activation of peripheral CB1Rs contributes to diet-induced obesity (DIO) and its hormonal/metabolic consequences. Here, we describe the chemical modification of currently available CB1R blocking drugs and present novel nanotechnology-based drug delivery systems to reduce their brain penetration and increase their oral bioavailability. Methods: Three novel compounds (BB1-08, BB1-09, BB1-10) were synthesized and characterized by using LC-MS/MS, HPLC, and H-NMR analyses. CB1R binding and activity and brain penetration, and behavioral activity were assessed—efficacy of the novel drugs to ameliorate obesity and its metabolic complications were determined in DIO mice. Two novel nano-drug delivery systems were designed, and we tested their ability to affect bioavailability and brain penetration in vivo.

Chronic 28-day intraperitoneal treatment of DIO mice with BB1-08, BB1-09, and BB1-10 revealed surprising results. BB1-08, BB1-09, and BB1-10 demonstrated high affinity for human CB1R, having Ki values of 28.7, 55.2, and 46.7 nM, respectively. All three molecules reduced GTPγS binding, suggesting inverse agonism properties. Low brain levels of the compounds following acute administration to mice were associated with negligible CNS-mediated behavioral effects. Whereas BB1-08 was found to be ineffective in ameliorating the metabolic syndrome due to unfavorable pharmacokinetics, both BB1-09 and BB1-10 reduced body weight, food intake, fat mass, and improved glucose homeostasis dyslipidemia, and kidney function. Additionally, improved bioavailability of BB1-10 was achieved by using nanotechnology-based drug delivery systems.