Ulrich Widmer

A non peptidic corticotropin releasing factor receptor antagonist attenuates fever and exhibits anxiolytic-like activity.

The multiple actions of corticotropin-releasing factor (CRF) on neuroendocrine and behavioural functions can now be examined using new, high affinity, non peptidic antagonists which exhibit central activity upon systemic application. We have shown that compound CP 154,526 (butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]amine) displaces [125I][Tyr0]CRF from rat hippocampal CRF receptors (IC50 = 0.5 nM) and from pituitary CRF receptors (IC50 = 0.04 nM). The same compound inhibits in a concentration-dependent manner the ovine CRF (0.1 microM)-stimulated adenylate cyclase activity in membranes of a mouse pituitary adenoma cell line, AtT20, with an IC50 value of 50 nM. Systemic application of the CRF receptor antagonist (0.16 mg/kg i.p.) blocked recombinant human interleukin-1 beta 5 micrograms/kg i.p.) induced fever in rats. The CRF receptor antagonist CP 154,526 (1 mg/kg i.p.) also exhibited signs of anxiolytic-like activity in the elevated plus-maze test in rats.

Behavioral profile of the 5HT1A receptor antagonist (S)-UH-301 in rodents and monkeys

The effects of the new 5HT1A receptor antagonist (S)-UH-301 were investigated in several neurological and behavioral tests in rodents and monkeys. By itself, (S)-UH-301 was found to decrease palatable food consumption in rats, to exhibit anticonvulsant activity in mice, and anxiolytic-like properties in two rodent models of anxiety (light-dark test and elevated plus-maze test). (S)-UH-301 antagonized various symptoms and behaviors induced by the selective 5HT1A receptor agonist 8-OH-DPAT, such as lower lip retraction and flat body posture in rats, hyperphagia for palatable food in rats, and displacement activities (considered as indices of anxiety) in squirrel monkeys. These results further characterize (S)-UH-301 as an in vivo active 5HT1A receptor antagonist and suggest that this antagonistic activity might confer the compound with anxiolytic-like properties.

Synthesis, pharmacology and therapeutic potential of 10-methoxypyrazino[1,2-a]indoles, partial agonists at the 5HT2C receptor

Summary A series of new 10-methoxypyrazino[1,2- a ]indoles has been prepared and shown to be 5HT 2C receptor ligands. The studied compounds 10a–j were found to act as partial agonists at the 5HT 2C receptor, binding with high affinity and moderate selectivity versus 5HT 1A and 5HT 2A receptors, but inducing only a submaximal increase in phosphoinositol formation. Compound 10j was demonstrated to be active in animal models of obsessive-compulsive disorder, depression and panic anxiety.