A screening hit was used as the basis for the core structure of a new series of acylglycinamide GlyT-1 inhibitors. Investigation of the SAR around four areas of diversity used facile chemistry to prepare compounds quickly. By focussing on reducing the lipophilicity and improving the aqueous solubility in the series we were able to prepare a compound (17e) with a good level of activity at GlyT-1, selectivity over GlyT-2 and moderate oral bioavailability.

This communication reports SARs for the first orexin-1 receptor antagonist series of 1-aryl-3-quinolin-4-yl and 1-aryl-3-naphthyridin-4-yl ureas. One of these compounds, 31 (SB-334867), has excellent selectivity for the orexin-1 receptor, blood–brain barrier permeability and shows in vivo activity following ip dosing.

Rationale: Orexins A and B have recently been discovered and shown to be derived from prepro-orexin, primarily expressed in the rat hypothalamus. Orexin-A has been ascribed a number of in vivo functions in the rat after intracerebroventricular (ICV) administration, including hyperphagia, neuroendocrine modulation and, most recently, evidence for a behavioural response characterised by an increase in grooming. Objectives: Here, we have investigated the orexin-receptor subtypes involved in the grooming response to orexin-A (3 μg, ICV) in the rat. Methods: Male rats, habituated to clear Perspex behavioural observation boxes, were pretreated with antagonists with mixed selectivity for OX1, OX2, 5-HT2B and 5-HT2C receptor subtypes prior to the administration of orexin-A and the intense grooming response elicited by this peptide assessed. Results: Pretreatment of rats with a mixed OX1/5-HT2B/2C receptor antagonist 1-(4-methylsulfanylphenyl)-3-quinolin-4-ylurea (SB-284422), revealed a significant, but incomplete, blockade of orexin-A-induced grooming. Despite the low potency of orexin-A at 5-HT2B and 5-HT2C receptors in vitro (pKi<5), studies were undertaken to determine whether downstream 5-HT2B or 5-HT2C receptors mediate in the grooming-elicited by orexin-A. Whilst the selective 5-HT2B receptor antagonist, SB-215505 (3 mg/kg, PO, 5-HT2B, pKi=8.58; OX1, pKB<5.15) failed to effect orexin-A-induced grooming, the selective 5-HT2C receptor antagonist, SB-242084 (1 mg/kg, IP, 5-HT2C, pKi=8.95; OX1, pKB<5.1) potently antagonised the grooming response to this peptide. This suggested that the partial blockade of orexin-A-induced grooming obtained with SB-284422 might be attributable to its 5-HT2C and/or OX1 receptor blocking activity. However, complete blockade of orexin-A-induced grooming by the subsequently identified selective OX1 receptor antagonist 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea hydrochloride, SB-334867-A (OX1, pKB=7.4; OX2, pKB=5.7), devoid of appreciable affinity for either 5-HT2B (pKi<5.3) or 5-HT2C (pKi<5.4) receptors, provides the first definitive evidence that a central behavioural effect of orexin-A (grooming) is mediated by OX1 receptors. Conclusions: This data suggests that orexin-A indirectly activates 5-HT2C receptors downstream from OX1 receptors to elicit grooming in the rat. The use of SB-334867-A in vivo will enable the role of OX1 receptors within the rat central nervous system to be further characterised.

RATIONALE:Orexin-A and orexin-B are hypothalamic neuropeptides derived from a 130-amino acid precursor, prepro-orexin, and are potent agonists at both the orexin-1 (OX1) and orexin-2 (OX2) receptors. Orexin-A has been ascribed a number of in vivo functions in the rat after intracerebroventricular (ICV) administration, including hyperphagia, neuroendocrine modulation and a role in the regulation of sleep-wake function. The in vivo role of orexin-B is not as clear.OBJECTIVES:To investigate the behavioural, endocrine and neurochemical effects of orexin-B in in-vivo tests. In a number of experiments, these effects were compared with those of orexin-A.METHODS:Experiments were carried out in male, Sprague-Dawley rats with a guide cannula directed towards the lateral ventricle. The effects of orexin-B (ICV) upon grooming behaviour were compared with those of orexin-A. The effects of orexin-B upon the motor activity response to both novel and familiar environments were assessed in an automated activity monitor. Orexin-B was tested upon startle reactivity and body temperature. Further, plasma hormones and [DOPAC+ HVA]/[DA] and [5-HIAA]/[5-HT] ratios in six brain areas were measured 40 min post-orexin-B or orexin-A.RESULTS:The clearest behavioural response to orexin-B was increased motor activity in both novel and familiar environments. Orexin-B-induced hyperactivity was blocked by an OX1 receptor antagonist, SB-334867-A, implicating OX1 receptors in this behavioural response. In common with orexin-A, orexin-B reduced plasma prolactin and failed to influence startle reactivity. However, in contrast with orexin-A, orexin-B increased head grooming but failed to cause a robust whole body grooming response or increase plasma corticosterone levels. Further, orexin-B, but not orexin-A, increased plasma TSH and increased hypothalamic and striatal [5-HIAA]/[5-HT] ratios.CONCLUSIONS:The present study has demonstrated a number of behavioural, neuroendocrine and neurochemical effects of orexin-B that distinguish it from orexin-A. Further, we have demonstrated a role for OX1 receptors in the actions of orexin-B upon motor activity.

A compound of formula (I) ** (Formula) ** in which: one of X and Y is N and the other is CH; Z represents oxygen or sulfur; R1 represents alkyl (1-6C), alkenyl (2-6C) or alkoxy (1-6C) alkyl, any of these may be optionally substituted; halogen, R8 NR9 CO- or R10CO-, R2, R3, R4, R5 and R6 independently represent (1-6C) alkyl, (2-6C) alkyl, (1-6C) alkylthio or (1-6C) , any of these may be optionally substituted; hydrogen, halogen, nitro, cyano, aryloxy, alkyloxy aryl (1-6C), aryl (1-6C) alkyl, R8CO-, R8SO2NH-, R8SO2O-, R8CON (R11) -, NR9R10-, NR9R10CO-, -COOR 9, R11C (= NOR8), heterocycle or alkyl heterocycle (C1-6); or an adjacent pair of R2, R3, R4, R5 and R6 together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring substituted optionally; R7 is alkyl (C1-6), (C2-6) alkoxy (C1-6) alkylthio or (1-6C) alkyl, any of these may be optionally substituted; halogen, hydroxy, nitro, cyano, NR9 R10-, NR9R10CO-, N3, -OCOR9 or R8CON (R11) -; R8 is (1-6C) alkyl, (2-6C) alkenyl, heterocycle, alkyl heterocycle (1-6C) alkenyl heterocycle (2-6C), aryl, aryl (1-6C) alkenyl or aryl (C1-6 ), any of these may be optionally substituted; R9 and R10 independently represent hydrogen, alkyl (C1-6), (C2-6) alkyl, heterocycle (1-6C), aryl or aryl (C1-6) alkyl, any of which may be optionally substituted ; R11 is hydrogen or (1-6C) alkyl; n is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof.

A variety of evidence implicates the orexins, especially orexin-A, in the regulation of food intake, but it has not been established whether this effect is mediated by the orexin-1 or orexin-2 receptor. In the present study, a selective orexin-1 receptor antagonist, 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea hydrochloride (SB-334867-A), was administered intraperitoneally to rats under various conditions, and food consumption was subsequently measured over 24 h. In male rats, a single dose of SB-334867-A (30 mg/kg, i.p.) given during the light phase reduced both orexin-A-induced food intake (7 nmol, i.c.v.) and feeding stimulated by an overnight fast for 4 h. When given at the start of the dark phase, food consumption was reduced in both male and female rats over 24 h. Daily injections at the start of the dark phase for 3 days reduced natural feeding in male rats over 24 h on days one and three. These findings demonstrate direct inhibition of orexin-A induced food intake with a selective orexin-1 receptor antagonist. Furthermore, the suppression of nocturnal feeding and food intake stimulated by an overnight fast supports other evidence that orexin-A is involved in the regulation of natural feeding and suggests that orexin-1 receptor antagonists could be useful in the treatment of obesity.

A series of 2-[(substituted)phenyl]-5-[1-(2-phenylazacycloheptyl)methyl]-1H-pyrroles (8 – 15) has been prepared to investigate the effect on affinity and selectivity for the dopamine D3 receptor of modifying the substituent in the phenyl ring at the 2-position of the pyrrole. Sulfonate 7 and sulfonamides 12, 14, 15 were shown to have high affinities (pKi's 8.0 – 8.7) and selectivities (100 – 150-fold) for the D3 over the D2 receptor.