TDIQ

Abstract: Tetrahydro-1,3-dioxolo(4,5-g)isoquinoline (TDIQ) is a conformationally restricted phenylalkylamine related in structure to amphetamine and N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) that does not act as a locomotor stimulant. To further evaluate this agent, a group of six rats was trained to discriminate 5.0 mg/kg of TDIQ from vehicle and tests of stimulus generalization were conducted to define the stimulus. The TDIQ stimulus (ED50=0.9 mg/kg) failed to generalize to the central stimulants (+)amphetamine, methylphenidate or ()ephedrine but, curiously, generalized to cocaine (ED50=1.5 mg/kg). When administered to rats (n=5) trained to discriminate 1.0 mg/kg of (+)amphetamine from vehicle, TDIQ produced a maximum of 7% (+)amphetamine-appropriate responding, whereas when administered to rats (n=7) trained to discriminate 4.0 mg/kg of ()ephedrine from vehicle, TDIQ produced a maximum of 57% drug-appropriate responding. Administration of MDMA to TDIQ-trained animals resulted in 76% TDIQ-appropriate responding. Tests of stimulus generalization were also conducted with fenfluramine, nisoxetine, clenbuterol, imipramine and buspirone, and tests of antagonism were conducted with haloperidol and R(+)SCH-23390 using the TDIQ-trained animals. Results were inconclusive in that these agents either failed to completely substitute for or failed to completely antagonize the TDIQ stimulus. Nevertheless, the generalization seen with cocaine, the partial generalization seen with ()ephedrine, MDMA, nisoxetine, clenbuterol and buspirone and the partial antagonism seen with haloperidol suggest that TDIQ might be acting through a mixed mechanism that involves adrenergic, dopaminergic and/or serotonergic systems. Given that TDIQ is an agent that seems to differentiate among the stimuli produced by amphetamine, methylphenidate, ephedrine and cocaine, it is proposed that further tests be undertaken, using animal models of cocaine abuse, to evaluate the potential usefulness of TDIQ as pharmacotherapy in cocaine dependence. D 2002 Elsevier Science Inc. All rights reserved.

Abstract: There is considerable evidence that α 2 -adrenergic receptor activity exerts a pivotal role in initiation of feeding behavior. The appetite suppressant and monoamine release effects of TDIQ (5,6,7,8-tetrahydro-1,3-dioxolo[4,5- g ]isoquinoline), a putative selective α 2 -adrenergic compound, were compared to those of fenfluramine, a reference drug that produces an anorectic effect via presynaptic release and reuptake inhibition of serotonin. The drugs were administered to two groups of mice that had learned to consume either sweet milk or chocolate pellets (i.e. “snacks”) during the low-activity/reduced-feeding “light” portion of their light/dark cycle. The selectivity of the drugs to suppress the consumption of snacks was determined by comparing doses of each drug that inhibited the animals' consumption of snacks to doses of each drug that have been shown, or were shown, to impact the motor (i.e. locomotor, rotarod, and inclined-screen side effect-like tests) or conditioned taste aversion (CTA) behavior of mice. An evaluation of TDIQ as a releaser of monoamines was determined in rodent brain synaptosomes. The administration of TDIQ or fenfluramine inhibited the consumption of the snacks, and a comparison of their ED 50 doses indicated that TDIQ is about 3 times more potent than fenfluramine (1.3 mg/kg vs. 4.2 mg/kg, respectively) in the sweet milk test and almost equipotent to fenfluramine (19.4 mg/kg vs. 18.4 mg/kg, respectively) in the chocolate pellet assay. The selectivity of the appetite suppressant effect of TDIQ was differentiated from that of fenfluramine on the basis that TDIQ exhibited a wide separation between its dose–response effects that suppressed snack consumption and its minimal effects in tests that measured behavioral impairment. Moreover, TDIQ was distinguished from fenfluramine in that it displayed very low potencies as a presynaptic releaser of monoamines. Finally, TDIQ (0.3 mg/kg–30.0 mg/kg) did not induce a conditioned taste aversion. TDIQ may represent a novel chemical entity that exhibits a significantly favorable therapeutic-like (i.e. appetite suppressant) effect to side effect-like ratio.

Abstract: 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., α2A-, α2B-, and α2C-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.

Abstract: Numerous studies have suggested that the central α 2 -adrenergic receptor system may exert an important role in some types of human anxiety. The anxiolytic-like activity and potential side effect-like activities of the novel and purported α 2 -adrenergic compound TDIQ (5,6,7,8-1,3-dioxolo[4,5- g ]isoquinoline) were compared to those of the anxiolytic drugs diazepam and buspirone, and the nonselective α 2 -adrenergic agent clonidine. Anxiolytic-like behavior was assessed in an object (marble)-burying assay, a selective test for the evaluation of known anxiolytics and identification of putative antianxiety compounds, that used mice housed either alone or in groups (5/cage). The rodents' antianxiety-like effect was defined as dose-related increases in the number of marbles that remained uncovered in their bedding material without concomitant disruption of their motor activities. Rotarod and inclined screen procedures were employed as potential indicators of side effects. An additional test monitored the heart rate (HR) and blood pressure (BP) of mice after the intravenous (IV) administration of doses of TDIQ. The reference compounds inhibited marble-burying behavior in a dose-related manner and produced various degrees of impairment in the side effect tests. TDIQ also inhibited object burying and displayed a wide separation between doses that produced anxiolytic-like activity and doses that produced some, if any, disruption of coordinated movement and/or motor activity. Moreover, the IV administration of TDIQ, up to 10 mg/kg, produced negligible effects on the HR and BP of mice. TDIQ could be a lead candidate for a new type of structural compound in the treatment of certain forms of anxiety.