SB 242084, a Selective and Brain Penetrant 5-HT2C Receptor Antagonist
Section snippets
Cell culture
Human neuroblastoma cells (SH-SY5Y) were stably transfected with the human cloned 5-HT2C receptor (Newton et al., 1996). SH-SY5Y cells were maintained in Dulbecco's modified Eagle's medium (DMEM) containing 10% dialyzed fetal calf serum (FCS), geneticin (0.4 mg/ml) and non-essential amino acids in a humidified incubator at 37°C, gassed with 5% CO2. The cells were harvested by trypsinization.
Binding assays
In all assays (for details see Table 1), SB 242084 was dissolved in polyethylene glycol (PEG): dimethyl
Receptor binding profile
SB 242084 had high affinity for the cloned human 5-HT2C receptor with a pKi of 9.0 and a slope value close to unity (0.95 ± 0.06 not significant, n.s.). The compound had a much lower affinity for the human cloned 5-HT2B (pKi 7.0, slope 1.2 ± 0.07 n.s) and 5-HT2A (pKi 6.8, slope 1.38 ± 0.21 n.s.). At all other receptors tested, SB 242084 had a lower affinity (Table 2). However, slope values for the 5-HT1B (2.1 ± 0.5, p < 0.05), 5-HT1D (1.8 ± 0.2, p < 0.01), 5-HT1E (1.5 ± 0.1, p < 0.05), 5-HT1F
DISCUSSION
Receptor binding studies demonstrate that SB 242084 has a high affinity for the 5-HT2C receptor with 100-fold selectivity over the 5-HT2B receptor and at least 100-fold selectivity over all other receptors tested, including the 5-HT2A receptor subtype. This contrasts with previously reported 5-HT2C receptor antagonists such as SB 200646A (Kennett et al., 1994), SB 206553 (Kennett et al., 1996b) and SDZ SER082 (Nozulak et al., 1994) which are all displayed similar affinities for the 5-HT2B and
References (52)
- et al.
Nonlinear regression using spreadsheets
Trends in Pharmacological Science
(1995) - et al.
d-Fenfluramine and d-norfenfluramine-induced hypophagia: differential mechanisms and involvement of postsynaptic 5-HT receptors
European Journal of Pharmacology
(1993) - et al.
m-Chlorophenylpiperazine as a probe of serotonin function
Biology and Psychiatry
(1991) - et al.
New mouse 5-HT2-like receptor: expression in brain, heart and intestine
FEBS Letters
(1992) - et al.
Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations
Epilepsy Research
(1988) - et al.
5-HT2C receptor agonists and antagonists in animal models of anxiety
European Neuropharmacology
(1995) - et al.
5-HT2C receptor agonists exhibit antidepressant-like properties in the anhedonia model of depression
European Neuropsychopharmacology
(1996) - et al.
Distribution of the serotonin 5-HT2 receptor family mRNAs:comparisons between 5-HT2A and 5-HT2C receptors
Molecular Brain Research
(1994) - et al.
Cloning and functional characterization of the human 5-HT2B serotonin receptor
FEBS Letters
(1994) - et al.
Pharmacology of human dopamine D3 receptor expressed in mammalian cell lines: comparison with D2 receptor
European Journal of Pharmacology
(1992)
European Journal of Pharmacology
Cloning of another human serotonin receptor (5-HT1F): a fifth 5-HT1 receptor subtype coupled to the inhibition of adenylate cyclase
Proceedings of the National Academy of Science U.S.A.
The pharmacology and distribution of human2B (5-HT2B) receptor gene products: comparison with 5-HT2A and 5-HT2C receptors
British Journal of Pharmacology
Further characterisation of human D2 and D3 dopamine receptors: GppNHp shifts are explained by the presence of more than one binding site in each clone
British Journal of Pharmacology
[125I]-SB 207710, a potent, selective radioligand for 5-HT4 receptors
British Journal of Pharmacology
Relationship between inhibition constant (Ki) and the concentration of inhibitor which causes 50% inhibition (IC50) Of an enzymatic reaction
Biochemistry and Pharmacology
Inverse agonist activity of beta-adrenergic antagonists
Molecular Pharmacology
Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay and physiological dose-response curve
American Journal of Physiology
Evidence that blockade of post-synaptic 5-HT1 receptors elicits feeding in satiated rats
Psychopharmacology
Can social interaction be used to measure anxiety?
British Journal of Pharmacology
Evidence for expression of the 5-HT2B receptor mRNA in rat brain
British Journal of Pharmacology
Increased food intake in satiated rats induced by the 5-HT antagonists methyserrgide, metergoline and ritanserin
Psychopharmacology
Cited by (479)
Role of 5-HT<inf>1A</inf> receptors in the basolateral amygdala on 3,4-methylenedioxymethamphetamine-induced prosocial effects in mice
2023, European Journal of Pharmacology“Selective” serotonin 5-HT<inf>2A</inf> receptor antagonists
2022, Biochemical PharmacologyCannabidiol and the corticoraphe circuit in post-traumatic stress disorder
2021, IBRO Neuroscience Reports5-HT2C agonists and antagonists block different components of behavioral responses to potential, distal, and proximal threat in zebrafish
2021, Pharmacology Biochemistry and Behavior