TDIQ (5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline) inhibits the consumption of "snacks" in mice.
There is considerable evidence that alpha2-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 alpha2-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 ED50 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.
Young
Richard
R
Department of Medicinal Chemistry, School of Pharmacy, Box 980540, Virginia Commonwealth University, Richmond, VA 23298, USA. ryoung@vcu.edu
Rothman
Richard B
RB
Rangisetty
Jagadeesh B
JB
Partilla
John S
JS
Dukat
Malgorzata
M
Glennon
Richard A
RA
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D005247:Feeding Behavior / Q000187:drug effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009638:Norepinephrine / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*
C451062:5,6,7,8-tetrahydro-1,3-dioxolo(4,5-g)isoquinoline; D044005:Tetrahydroisoquinolines; D012701:Serotonin; D004298:Dopamine; D009638:Norepinephrine