SB-243213; a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety
by
Wood MD, Reavill C, Trail B, Wilson A, Stean T, Kennett GA,
Lightowler S, Blackburn TP, Thomas D, Gager TL,
Riley G, Holland V, Bromidge SM, Forbes IT, Middlemiss DN.
Department of Neuroscience Research,
SmithKline Beecham Pharmaceuticals,
New Frontiers Science Park,
Third Avenue, Harlow Essex,
CM19 5AW, UK.
martyn_wood-1@sbphrd.com
Neuropharmacology. 2001 Aug;41(2):186-99


ABSTRACT

SB-243213 (5-methyl-1-[[-2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline hydrochloride) is a new, selective 5-hydroxytryptamine (5-HT)2C receptor inverse agonist. SB-243213 has high affinity for the human 5-HT2C receptor (pK(i) 9.37) and greater than a 100-fold selectivity over a wide range of neurotransmitter receptors, enzymes and ion channels. In in vitro functional studies, SB-243213 acted as an inverse agonist at the human 5-HT2C receptor with a pK(b) of 9.8. In in vivo studies, SB-243213 was a potent inhibitor of central 5-HT2C receptor-mediated function in rats, blocking meta-chlorophenylpiperazine-induced hypolocomotion with an ID50 of 1.1 mg/kg p.o. and a long duration of action (>8 h). In rats, SB-243213 exhibited anxiolytic-like activity in both the social interaction and Geller-Seifter conflict tests. Importantly, unlike diazepam, chronic administration of SB-243213 did not result in the development of either tolerance to the anxiolytic-like effects or withdrawal anxiogenesis. Furthermore, in rodents, SB-243213 did not affect seizure threshold, did not increase body weight or induce catalepsy, but attenuated the haloperidol-induced catalepsy. SB-243213 did not affect amphetamine-, MK-801- or phencyclidine-induced hyperactivity. In conclusion, SB-243213 may possess an improved anxiolytic profile compared to benzodiazepines. SB-243213 also modulates dopaminergic transmission, lacks pro-psychotic properties and may have utility in the treatment of schizophrenia and motor disorders.
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Benzodiazepines
Future anxiolytics
Making animals cry
The role of melatonin
Anxiety and depression
Anxious golden hamsters
Better anti-anxiety drugs
Anxiolytics/antidepressants
Fluoxetine (Prozac) and 5-HT2c
The serotonin 5-HT2C receptors
Agomelatine (Valdoxan): review
Neurobiology and genetics of anxiety


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