Discovery and SAR of potent, orally available and brain-penetrable 5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen- and 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen derivatives as neuropeptide Y Y5 receptor antagonists.

Combination of structural elements from a potent Y5 antagonist (2) with thiazole fragments that exhibit weak Y5 affinities followed by lead optimisation led to the discovery of (5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino and (4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino derivatives. Both classes of compounds are capable of delivering potent and selective orally and centrally bioavailable NPY Y5 receptor antagonists.

MSG lesions decrease body mass of suckling-age rats by attenuating circadian decreases of energy expenditure.

Suckling-age rats display endogenous circadian rhythmicity of metabolic rate (MR) with energy-saving, torpor-like decreases, which are sympathetically controlled and suppressed by leptin treatment. We investigated whether neonatal monosodium glutamate (MSG) treatment, known to cause arcuate nucleus damage and adult-age obesity, alters energy balance in the first two postnatal weeks. Continuously recorded MR and core temperatures (T(c)) show that MSG treatment disinhibits the periodic, sympathetically controlled, energy-saving drops of T(c) and MR. Increased energy expenditure thus explains reduced body fat at normal lean body mass found in MSG-treated pups artificially nourished identically to controls. In MSG-treated mother-reared pups, lean body mass is additionally reduced, suggesting that MSG also reduces suckling. Plasma leptin levels are similar in controls and MSG-treated pups but higher per unit of fat mass in the latter. We conclude that the postweaning development of MSG obesity and depressed thermogenesis are preceded by an early phase of increased energy expenditure with decreased fat deposition during suckling age and hypothesize cell damage in the arcuate nucleus to be involved in both.