Amanda Johns

A selective orexin-1 receptor antagonist reduces food consumption in male and female rats.

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.

1,3-Biarylureas as Selective Non-peptide Antagonists of the Orexin-1 Receptor

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.

N-(substituted-phenyl) piperazines: antagonists with high binding and functional selectivity for dopamine D4 receptors

Abstract A series of N-(substituted-phenyl) piperazine derivatives was prepared as selective antagonists of the dopamine D 4 receptor. Many analogues possessed a binding selectivity of over 100 fold for D 4 over D 2 receptors. In functional studies in the microphysiometer, compound 24 showed a selectivity over dopamine D 2 receptors of greater than 1000 fold.

A concise enantioselective synthesis of the AB ring system of the manzamine alkaloids by ring-closing enyne metathesis

The AB ring system found in the manzamine A and related alkaloids has been prepared from (−)-quinine by a short enantioselective route. The key step in the sequence is a ruthenium-catalysed ring-closing enyne metathesis re action which delivers a bicyclic diene in good yield. The functionality required for further elaboration of the AB system has been installed by sequential regioselective hydroboration and stereoselective catalytic aminohydroxylation.

2-[(substituted)phenyl]-5-[1-(2-phenylazacycloheptyl)methyl]-1H-pyrroles with high affinity and selectivity for the dopamine D3 receptor

Abstract A series of 2-[(substituted)phenyl]-5-[1-(2-phenylazacycloheptyl)methyl]-1 H -pyrroles ( 8 – 15 ) has been prepared to investigate the effect on affinity and selectivity for the dopamine D 3 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 (pKis 8.0 – 8.7) and selectivities (100 – 150-fold) for the D 3 over the D 2 receptor.

The synthesis of pyrazolo[4,3-c]- and imidazo[4,5-c]-Aryl[e]fused pyridines as structural analogues of 4-aminonicotinoates

Abstract A series of 4-aminobenzothienopyridine-3-carboxylates 4 to 10 has been prepared and the SAR of these GABA A modulators discussed. Replacement of the 4-aminonicotinoate moiety by imidazo [4,5- c ] ring fusion provides potent bioisosteres 12 to 14 .

Acylglycinamides as inhibitors of glycine transporter type 1.

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.