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 degrees 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 (CRF2 beta) 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 CRF2 beta receptor.