SB-243213; a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety

Wood, Martyn; Reavill, Charlie; Trail, Brenda; Wilson, Alex W.; Stean, Tania O.; Kennett, Guy A.; Lightowler, S.; Blackburn, T.P.; Thomas, D R; Gager, Tracey; Riley, Graham J.; Holland, Vicky; Bromidge, Steven M.; Forbes, Ian J.; Middlemiss, D.N.

doi:10.1016/s0028-3908(01)00054-5

Cited by 96 publications

(63 citation statements)

References 34 publications

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“…Additionally, many typical and atypical antipsychotic drugs have high 5-HT 2C receptor affinities (Canton et al, 1990;Roth et al, 1992), and many antipsychotic drugs are potent 5-HT 2C inverse agonists (Herrick-Davis et al, 2000;Rauser et al, 2001). Finally, 5-HT 2C knockout mice are resistant to the anorectic effects of fenfluramine (Vickers et al, 1999), although chronic administration of potent and selective 5-HT 2C antagonists does not induce weight gain in rats (Wood et al, 2001). The present study clearly demonstrates that 5-HT 2C affinity does not predict weight gain among this group of typical and atypical antipsychotic drugs.…”

Section: Discussionmentioning

confidence: 99%

H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs

Kroeze

Hufeisen

Popadak

et al. 2003

Neuropsychopharmacol

703

494

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As a result of superior efficacy and overall tolerability, atypical antipsychotic drugs have become the treatment of choice for schizophrenia and related disorders, despite their side effects. Weight gain is a common and potentially serious complication of some antipsychotic drug therapy, and may be accompanied by hyperlipidemia, hypertension and hyperglycemia and, in some extreme cases, diabetic ketoacidosis. The molecular mechanism(s) responsible for antipsychotic drug-induced weight gain are unknown, but have been hypothesized to be because of interactions of antipsychotic drugs with several neurotransmitter receptors, including 5-HT 2A and 5-HT 2C serotonin receptors, H 1 -histamine receptors, a 1 -and a 2 -adrenergic receptors, and m3-muscarinic receptors. To determine the receptor(s) likely to be responsible for antipsychotic-drug-induced weight gain, we screened 17 typical and atypical antipsychotic drugs for binding to 12 neurotransmitter receptors. H 1 -histamine receptor affinities for this group of typical and atypical antipsychotic drugs were significantly correlated with weight gain (Spearman r ¼ À0.72; po0.01), as were affinities for a 1A adrenergic (r ¼ À0.54; po0.05), 5-HT 2C (r ¼ À0.49; po0.05) and 5-HT 6 receptors (r ¼ À0.54; po0.05), whereas eight other receptors' affinities were not. A principal components analysis showed that affinities at the H 1 , a 2A , a 2B , 5-HT 2A , 5-HT 2C , and 5-HT 6 receptors were most highly correlated with the first principal component, and affinities for the D 2 , 5-HT 1A , and 5-HT 7 receptors were most highly correlated with the second principal component. A discriminant functions analysis showed that affinities for the H 1 and a 1A receptors were most highly correlated with the discriminant function axis. The discriminant function analysis, as well as the affinity for the H 1 -histamine receptor alone, correctly classified 15 of the 17 drugs into two groups; those that induce weight gain and those that do not. Because centrally acting H 1 -histamine receptor antagonists are known to induce weight gain with chronic use, and because H 1 -histamine receptor affinities are positively correlated with weight gain among typical and atypical antipsychotic drugs, it is recommended that the next generation of atypical antipsychotic drugs be screened to avoid H 1 -histamine receptors.

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Section: Discussionmentioning

confidence: 99%

H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs

Kroeze

Hufeisen

Popadak

et al. 2003

Neuropsychopharmacol

703

494

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“…WAY-100635 has selective 5-HT 1A receptor antagonist activity at the doses used in this study (Prinssen et al, 1999). The doses of SB-269970A were selected based on pharmacokinetic analysis (Hagan et al, 2000), doses of SB-243213A (5-methyl-1- [[2-[92-methyl-3-pyridyl0oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindone hydrochloride) were selected based on effects observed in a study by Wood et al, (2001).…”

Section: Drugsmentioning

confidence: 99%

“…SB-243213A is active in preclinical models of anxiety and has an improved anxiolytic profile compared with benzodiazepines (Wood et al, 2001;Blackburn et al, 2002). SB-243213A may also have antidepressant-like activity as it increased deep slow wave sleep quantity with similar effect to paroxetine (Smith et al, 2002).…”

Section: Effect Of Sb-243213amentioning

confidence: 99%

Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat

et al. 2009

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“…at a dose volume of 2 ml/ kg. Doses of SB-243213-A were chosen based on the robust effects observed in behavioral and electrophysiological studies (Wood et al, 2001;Blackburn et al, 2002). Dose of clozapine (10 mg/kg) was chosen based on previous in house studies showing robust effects on DA levels in other regions of the brain.…”

Section: Drug Treatmentsmentioning

confidence: 99%

“…The present study has investigated the effect of acute administration of clozapine on extracellular DA levels in core and shell subregions of the NAcc using in vivo microdialysis in the rat, and compared these effects to those of 5-methyl-1- [[2-[92-methyl-3-pyridyl0oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindone (SB-243213), a highly selective, brain penetrant, 5-HT 2C receptor antagonist (Bromidge et al, 2000;Wood et al, 2001). Furthermore, we have investigated the effect of chronic administration of both compounds (ie clozapine or SB-243213 for 8 and 21 days) on extracellular DA levels in the shell subregion of the NAcc.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Clozapine on Extracellular Dopamine Levels in the Shell Subregion of the Rat Nucleus Accumbens is Reversed Following Chronic Administration: Comparison with a Selective 5-HT2C Receptor Antagonist

Shilliam

Dawson

2004

Neuropsychopharmacol

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The clinical onset of both the therapeutic and side effects of antipsychotic drugs can take days/weeks to develop. Therefore, it is likely that adaptive changes in neurotransmission of key systems may only manifest upon chronic administration. Thus, using in vivo microdialysis we have evaluated the acute and chronic (21 days) effects of the atypical antipsychotic clozapine on nucleus accumbens (NAcc) dopamine (DA) output in the rat. Clozapine (10 mg/kg p.o.) produced an acute 60% increase in extracellular levels of DA in the shell but not the core subregion of the NAcc. This clozapine-induced effect was also apparent on day 8 (59% increase) of chronic administration. However, on day 22 (following 21 days chronic administration), clozapine-induced a significant decrease in extracellular DA levels (44% decrease). Since clozapine possesses significant affinity for the 5-HT 2C receptor these clozapine-induced effects were compared to those of SB-243213, a selective 5-HT 2C receptor antagonist. SB-243213 (10 mg/kg p.o.) had no effect on NAcc DA levels either acutely or following 21 days chronic administration. These data demonstrate that the atypical neuroleptic clozapine is more effective at eliciting changes in the shell vs the core subregion of the NAcc. In contrast, chronic treatment produces a time-dependent reduction in clozapineinduced DA efflux in the shell subregion. This selective temporal change in dopaminergic neurotransmission may be associated with the delayed therapeutic onset of antipsychotic activity. However, since SB-243213 had no effect on DA levels in the NAcc, it is likely that 5-HT 2C receptor antagonism alone is not the mechanism by which clozapine exerts is actions.

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SB-243213; a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety

Cited by 96 publications

References 34 publications

H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs

H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs

Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat

The Effect of Clozapine on Extracellular Dopamine Levels in the Shell Subregion of the Rat Nucleus Accumbens is Reversed Following Chronic Administration: Comparison with a Selective 5-HT2C Receptor Antagonist

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