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.
Lundkvist
J
J
Department of Neurochemistry and Neurotoxicology, Stockholm University, Sweden.
Chai
Z
Z
Teheranian
R
R
Hasanvan
H
H
Bartfai
T
T
Jenck
F
F
Widmer
U
U
Moreau
J L
JL
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005334:Fever / Q000188:drug therapy* / Q000209:etiology; D007375:Interleukin-1 / Q000009:adverse effects; D008297:Male; D051379:Mice; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000009:adverse effects; D014407:Tumor Cells, Cultured
D018712:Analgesics, Non-Narcotic; D014151:Anti-Anxiety Agents; C101628:CP 154526; D007375:Interleukin-1; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D011994:Recombinant Proteins