Chronic release of CRH and ACTH is believed to be directly or indirectly involved in many of the harmful physiological effects of chronic stress, such as excessive glucocorticoid release, stomach ulcers, anxiety, diabetes mellitus, osteoporosis, depression, and development of high blood pressure and consequent cardiovascular problems.

[1] Antalarmin is a non-peptide drug that blocks the CRH1 receptor, and, as a consequence, reduces the release of ACTH in response to chronic stress.

CP-154,526 also demonstrated a large volume of distribution (Vd) at 6.7 L/kg, indicating extensive binding of the drug to tissue in Sprauge-Dawley rats.

[6] In male Wistar rats given a 5 mg/kg dose (p.o) of CP-154,526, an oral bioavailability of 27% and high volume of distribution at 105 L/kg was determined, with an estimated total clearance (CLt) of 36 ml/min/kg.

[12] An extensive pharmacokinetic study of Antalarmin conducted in macaques reported an oral bioavailability of 19%, a total clearance of 4.5 L/hr/kg, and an elimination half-life of 7.8 hours following a 20 mg/kg administration (p.o.).

[17] Initial studies investigating CP-154,526 showed that the compound binds with high affinity to cortical and pituitary CRH receptors across several species.

Additionally, systemic administration of CP-154,526 fully antagonizes the effects of exogenous CRH on ACTH levels, cell firing in the locus coeruleus, and fear potentiation in animal models.

[20] When Antalarmin was administered to primates, it also inhibited increases in plasma ACTH, as well as prevented the anxiety response produced by a social stressor (e.g. presentation of another male in an unfamiliar environment).

Antalarmin was also shown to have electrophysiological effects by partially reversing the inhibition of neuronal firing in the dorsal raphe nucleus that occurs following intracerebroventricular (i.c.v) administration of CRH.

[3] Oral administration of Antalarmin (3–30 mg/kg) also significantly reduced immobility in a rat model of behavioral despair, with effects similar to the SSRI fluoxetine.

[27] Collectively, these results indicate that during stress, CRH leads to the activation of skin mast cells through the CRH1 receptor which triggers vasodilation and increased vascular permeability.

[35][36][37] Overall, additional research is needed to determine the therapeutic efficacy of Antalarmin and other CRH non-peptide antagonists in anxiety, depression, inflammation, neurodegenerative disease, and addiction.