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

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.

The human GABA(B1b) and GABA(B2) heterodimeric recombinant receptor shows low sensitivity to phaclofen and saclofen.

1. The aim of this study was to characterize the pharmacological profile of the GABA(B1)/GABA(B2) heterodimeric receptor expressed in Chinese hamster ovary (CHO) cells. We have compared receptor binding affinity and functional activity for a series of agonists and antagonists. 2. The chimeric G-protein, G(qi5), was used to couple receptor activation to increases in intracellular calcium for functional studies on the Fluorimetric Imaging Plate Reader (FLIPR), using a stable GABA(B1)/GABA(B2)/G(qi5) CHO cell line. [(3)H]-CGP-54626 was used in radioligand binding studies in membranes prepared from the same cell line. 3. The pharmacological profile of the recombinant GABA(B1/B2) receptor was consistent with that of native GABA(B) receptors in that it was activated by GABA and baclofen and inhibited by CGP-54626A and SCH 50911. 4. Unlike native receptors, the GABA(B1)/GABA(B2)/G(qi5) response was not inhibited by high microMolar concentration of phaclofen, saclofen or CGP 35348. 5. This raises the possibility that the GABA(B1)/GABA(B2)/G(qi5) recombinant receptor may represent the previously described GABA(B) receptor subtype which is relatively resistant to inhibition by phaclofen.

Simple O-acylated derivatives of lysergol and dihydrolysergol-I: synthesis and interaction with 5-HT2A, 5-HT2C and 5-HT1B receptors, and alpha1 adrenergic receptors.

A series of simple O-acylated derivatives of the naturally occurring clavine alkaloids lysergol and dihydrolysergol-I were synthesized and tested in-vitro for their ability to interact with 5-HT2A receptors in rat tail artery, 5-HT2C receptors in piglet choroid plexus, 5-HT1B receptors in guinea-pig iliac artery and alpha1-adrenergic receptors in rat aorta. In contrast to the classical ergoline 5-HT2A receptor antagonists methysergide and LY53857, the compounds produced competitive antagonism of the 5-HT response in rat tail artery. Affinities of ergolines 3-14 were higher (pA2 values of 7.33-8.40) than those of the parent alcohols lysergol (1) and dihydrolysergol-I (2), respectively. The introduction of an isopropyl substituent at the N(1) position of the compounds failed to enhance 5-HT2A receptor affinity. Compounds 3-14 exhibited lower affinities for alpha1-adrenergic receptors than for 5-HT2A receptors. In particular, those lysergol derivatives that had an isopropyl substituent at the N(1) position were highly specific 5-HT2A receptor antagonists (ratio 5-HT2A/alpha1 = 302-3548). Selected derivatives of lysergol (3-5, 9-11) which were assayed for radioligand binding at 5-HT2C receptors in piglet choroid plexus had affinities that were similar to those found in rat tail artery. Additionally, lysergol and its N(1)-unsubstituted derivatives were found to be partial agonists (alpha of 0.2-0.4) for 5-HT2C receptor-mediated inositol phosphate accumulation in piglet choroid plexus. On the other hand, analogues with an isopropyl substituent at N(1) showed no measurable agonist activity. The observation that N(1)-unsubstituted derivatives of lysergol possessed agonist properties at 5-HT2C receptors whereas their agonist activity at 5-HT2A receptors was marginal (alpha of 0.05 for compound 3 at 1 microM) or not measurable, suggests that these compounds have different abilities to cause conformational change at the two receptor types. Selected derivatives of lysergol (3-5, 9-11) which were examined as ligands for 5-HT1B receptors in guinea-pig iliac artery caused insurmountable blockade of the contractile effect of 5-HT. N(1)-isopropyl derivatives had 30-50-fold lower affinities for 5-HT1B receptors of this tissue than their N(1)-unsubstituted analogues. It is concluded that O-acylated derivatives of the clavine alkaloids lysergol and dihydrolysergol-I mimic therapeutically relevant ergolines due to the complexity of their pharmacological profile as partial agonists and antagonists at 5-HT2A, 5-HT2C and 5-HT1B receptors, and at alpha1-adrenergic receptors.

m-Chlorophenylpiperazine (mCPP) is an antagonist at the cloned human 5-HT2B receptor.

The behavioural effects of m-chlorophenylpiperazine (mCPP) in rats and its clinical effects in man are thought to be related to its action at 5-HT2B/2C receptors. However, although mCPP is a partial agonist at these subtypes in rat, its efficacy at human 5-HT2B/2C receptors is unknown. We therefore investigated the activity of mCPP at cloned human 5-HT2B and 5-HT2C receptors. mCPP was a partial agonist at the human 5-HT2C receptor but antagonized the human 5-HT2B receptor. Therefore, while supporting the proposal that at least some of the clinical effects of mCPP are likely to be mediated via stimulation of the 5-HT2C receptor, this study also suggests that any 5-HT2B receptor-mediated effects are more likely to result from receptor blockade than from receptor activation.