TDIQ (5,6,7,8–tetrahydro-1,3-dioxolo [4,5-g]isoquinoline): Discovery, Pharmacological Effects, and Therapeutic Potential

Chemically, TDIQ (5,6,7,8–tetrahydro-1,3-dioxolo[4,5-g]isoquinoline) can be viewed as a conformationally restricted phenylalkylamine that is related in structure to amphetamine but does not stimulate (or depress) locomotor activity in rodents. In radioligand binding studies TDIQ displays selective affinity for α₂-adrenergic receptor subsites (i.e., α_2A-, α_2B-, and α_2C-adrenergic receptors), and behavioral data suggest that it might exert an agonist (or partial agonist) effect at α₂-adrenergic receptors or interact at α₂-adrenergic heteroreceptors. Drug discrimination studies in rats indicate that TDIQ: (1) serves as a discriminative stimulus, (2) may be useful in the treatment of symptoms associated with the abuse of cocaine, and (3) exhibits a low potential for abuse. In addition, TDIQ exhibits a dose-dependent and wide dissociation between doses that produce an anxiolytic-like effect or an inhibition of “snack” consumption in mice and doses that produce minimal, if any, effects in tests that measure a potential for disruption of coordinated movement or motor activity. Also, TDIQ displays negligible effects on the heart rate (HR) and blood pressure (BP) of mice. Taken together, the preclinical data suggest that TDIQ exhibits a favorable ratio of therapeutic-like effects (anxiolytic, therapeutic adjunct in the treatment of cocaine abuse, and appetite suppression) to side effect-like activities (behavioral impairment, drug abuse, or adverse cardiovascular effect). As such, TDIQ could: (1) be a forerunner for a new type of chemical entity in the treatment of certain forms of anxiety and/or obesity and (2) serve as a structural template in the discovery and development of additional agents that might be selective for α₂-adrenergic receptors.