These findings contribute to evidence identifying the σ(1) receptor as a modulator of activity-induced spinal sensitization and pain hypersensitivity, and suggest σ(1) receptor antagonists as potential novel treatments for neuropathic pain.

Sigma (sigma) sites are a type of nonopiate receptor whose role has been associated with several behaviours, including anxiety, depression, analgesia, learning processes and psychosis. Although there are several known sigma receptor types, only the type I receptor (sigma 1) has been cloned. To uncover the in vivo relevance of sigma-receptors, we have generated knockout mice for sigma 1. Despite the broad expression pattern found for the sigma 1-gene, homozygous mutant mice are viable, fertile and do not display any overt phenotype, compared with their wild-type litter-mates, in mixed genetic backgrounds. However, a significant decrease in the hypermotility response has been measured in knockout mice upon challenge with (+)SKF-10 047, in agreement with the involvement of sigma 1-receptors in the induction of psychostimulant actions. The activity of sigma 2-receptors seems to be unaffected in sigma 1-mutant mice. These knockout mice could contribute to better understand the in vivo role of sigma-receptors.

Based on a medicinal chemistry guided hypothetical pharmacophore model, novel series of indolyl sulfonamides have been designed and prepared as selective and high-affinity serotonin 5-HT(6) receptor ligands. Furthermore, based on a screening approach of a discovery library, a series of benzoxazinepiperidinyl sulfonamides were identified as selective 5-HT(6) ligands. Many of the compounds described in this paper possess excellent affinities, displaying pK(i) values greater than 8 (some even >9) and high selectivities against a wide range (>50) of other CNS relevant receptors. First, structure-affinity relationships of these ligands are discussed. In terms of functionality, high-affinity antagonists, as well as agonists and even partial agonists, were prepared. Compounds 19c and 19g represent the highest-affinity 5-HT(6) agonists ever reported in the literature. These valuable tool compounds should allow for the detailed study of the role of the 5-HT(6) receptor in relevant animal models of disorders such as cognition deficits, depression, anxiety, or obesity.

1 E-6837 is a novel, selective and high-affinity 5-HT 6 receptor ligand (pK i : 9.13) which in vitro demonstrates partial agonism at a presumably silent rat 5-HT 6 receptor and full agonism at a constitutively active human 5-HT 6 receptor by monitoring the cAMP signaling pathway. 2 The effects of chronic treatment with E-6837 were determined in diet-induced obese (DIO)-rats on changes in body weight, food and water intake, plasma indices of comorbid risk factors, and weight regain on compound withdrawal. The centrally acting antiobesity drug, sibutramine, was used as the reference comparator. 3 Sustained body weight loss and decreased cumulative food intake of DIO-rats was observed with E-6837 (30 mg kg À1 , p.o., twice a day) during the 4-week treatment period. The onset of the E-6837 effect on body weight was slower than that of sibutramine (5 mg kg À1 , p.o.), while its maximal effect was greater, that is À15.7 versus À11.0%. 4 E-6837-induced weight loss was exclusively mediated by a decrease (31.7%) in fat mass, with a concomitant reduction (49.6%) in plasma leptin. Reduced obesity was also reflected in improved glycemic control. 5 Although weight regain occurred after withdrawal from either compound, the body weights after E-6837 (À6.6%) remained lower than after sibutramine (À3.8%) indicating that the greater efficacy of the former did not result in profound rebound hyperphagia/weight gain. 6 These results show that the 5-HT 6 receptor partial agonist, E-6837, is a promising new approach to the management of obesity with the potential to produce greater sustained weight loss than sibutramine.

Our findings demonstrate that E-6199 may be an effective hypnotic compound that promotes and improves NREMS, without producing EEG side effects, tolerance or withdrawal phenomena, when administered under chronic conditions.