A NON PEPTIDIC CORTICOTROPIN-RELEASING FACTOR-RECEPTOR ANTAGONIST ATTENUATES FEVER AND EXHIBITS ANXIOLYTIC-LIKE ACTIVITY

The multiple actions of corticotropin-releasing factor (CRF) on neuroe ndocrine and behavioural functions can now be examined using new, high affinity, non peptidic antagonists which exhibit central activity upo n systemic application. We have shown that compound CP 154,526 thylphe nyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine) displaces [I-125][Tyr(0)]C RF from rat hippocampal CRF receptors (IC50 = 0.5 nM) and from pituita ry CRF receptors (IC50 = 0.04 nM). The same compound inhibits in a con centration-dependent manner the ovine CRF (0.1 mu M)-stimulated adenyl ate cyclase activity in membranes of a mouse pituitary adenoma cell li ne, AtT20, with an IC50 value of 50 nM. Systemic application of the CR F receptor antagonist (0.16 mg/kg i.p.) blocked recombinant human inte rleukin-1 beta (5 mu g/kg i.p.) induced fever in rats. The CRF recepto r antagonist CP 154,526 (1 mg/kg i.p.) also exhibited signs of anxioly tic-like activity in the elevated plus-maze test in rats.