There is evidence that the metabolic effects of endocannabinoids are mediated by CB1 receptors in peripheral tissues. While prior attempts at generating CB1 receptor blockers have had serious neuropsychiatric side effects, inventors at NIH have discovered compounds that block CB1 receptors with reduced brain penetrance. In addition, some of these compounds also have a direct inhibitory effect on inducible nitric oxide synthase (iNOS), whereas another group of the compounds directly activates AMP kinas. These dual-target compounds may be useful for treating metabolic disease and related conditions such as obesity and diabetes and their complications, including liver or kidney fibrosis, without the dangerous the side effects.