Elsevier

Neuropharmacology

Volume 36, Issues 4–5, April–May 1997, Pages 609-620
Neuropharmacology

SB 242084, a Selective and Brain Penetrant 5-HT2C Receptor Antagonist

https://doi.org/10.1016/S0028-3908(97)00038-5Get rights and content

Abstract

SB 242084 has a high affinity (pKi 9.0) for the cloned human 5-HT2C receptor and 100- and 158-fold selectivity over the closely related cloned human 5-HT2B and 5-HT2A subtypes respectively. SB 242084 had over 100-fold selectivity over a range of other 5-HT, dopamine and adrenergic receptors. In studies of 5-HT-stimulated phosphatidylinositol hydrolysis using SH-SY5Y cells stably expressing the cloned human 5-HT2C receptor, SB 242084 acted as an antagonist with a pKb of 9.3, which closely resembled its corresponding receptor binding affinity. SB 242084 potently inhibited m-chlorophenylpiperazine (mCPP, 7 mgkg i.p. 20 min pre-test) -induced hypolocomotion in rats, a model of in vivo central 5-HT2C receptor function, with an ID50 of 0.11 mg/kg i.p., and 2.0 mg/kg p.o. SB 242084 (0.1–1 mg/kg i.p.) exhibited an anxiolytic-like profile in the rat social interaction test, increasing time spent in social interaction, but having no effect on locomotion. SB 242084 (0.1–1 mg/kg i.p.) also markedly increased punished responding in a rat Geller-Seifter conflict test of anxiety, but had no consistent effect on unpunished responding. A large acute dose of SB 242084 (30 mg/kg p.o.) had no effect on seizure susceptibility in the rat maximal electroshock seizure threshold test. Also, while SB 242084 (2 and 6 mg/kg p.o. 1 hr pre-test) antagonized the hypophagic response to mCPP, neither acute nor subchronic administration of the drug, for 5 days at 2 or 6 mg/kg p.o. twice daily, affected food intake or weight gain. The results suggest that SB 242084 is the first reported selective potent and brain penetrant 5-HT2C receptor antagonist and has anxiolytic-like activity, but does not possess either proconvulsant or hyperphagic properties which are characteristic of mutant mice lacking the 5-HT2C receptor. © 1997 Elsevier Science Ltd.

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

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