[D-Pro5]Corticotropin-releasing factor analogs as selective agonists at corticotropin-releasing factor receptors
| Autor: | Holly A. Thomas, Edward T. Wei, Jeffrey S. Price, Toshimitsu Kishimoto |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
Male
endocrine system medicine.medical_specialty Corticotropin-Releasing Hormone Biology Peptide hormone Receptors Corticotropin-Releasing Hormone Corticotropin-releasing hormone receptor 1 Cell Line Rats Sprague-Dawley Structure-Activity Relationship Adrenocorticotropic Hormone In vivo Internal medicine medicine Structure–activity relationship Animals Edema Humans Receptor Pharmacology chemistry.chemical_classification Sheep In vitro Amino acid Rats Endocrinology chemistry Second messenger system hormones hormone substitutes and hormone antagonists |
| Zdroj: | European journal of pharmacology. 306(1-3) |
| ISSN: | 0014-2999 |
| Popis: | Corticotropin-releasing factor (CRF) acts on at least two types of CRF receptors. To search for selective CRF receptor agonists, 37 ovine CRF analogs, systematically substituted with d -amino acids, were tested for inhibitory activity on edema induced in the pentobarbital-anesthetized rat paw by heat (immersion in 58°C water for 1 min). The activity of each analog, administered 21 nmol/kg i.v. 10 min before heat, was compared to published data on the analog's potency in stimulating adrenocorticotropin (ACTH) release from cultured rat pituitary cells. In general, a positive rank correlation was found between the anti-edema and neuroendocrine activities of these analogs, however, one outlier, [ d -Pro5]ovine CRF, exhibited greater selectivity for anti-edema activity. The human/rat analog of [ d -Pro5]CRF was synthesized and found to be equipotent to human/rat CRF for suppression of heat-edema. In cells transfected with two types of cloned CRF receptors, the intracellular cAMP response to [ d -Pro5]human/rat CRF was equipotent to human/rat CRF in the heart-muscle CRF (CRF2β) receptor assay but was five times less potent than human/rat CRF in the pituitary-central nervous system CRF (CRF1) receptor assay. We conclude that changing residue Pro5 in the CRF molecule from a l - to a d -configuration confers selectivity by decreasing second messenger activation at the CRF1 receptor whilst retaining full potency at the CRF2β receptor. |
| Databáze: | OpenAIRE |
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