The present study described the development of a novel CRH-R1 antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. Experiments conducted in our laboratories showed that the newly synthesized CRH-1R antagonist 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP) inhibited 125I-sauvagine binding to rat pituitary membranes and cloned hCRH-R1 with sub-nanomolar affinities, with no detectable activity at the CRH-R2 receptor or other common drug targets. Following oral administration to rats, MTIP inhibited 125I-sauvagine binding to rat cerebellar membranes ex vivo with an ED50 of app. 1.3 mg/kg and an oral bioavailability of 91.1%. Compared to other well characterized CRH-1R antagonists, namely R121919 and CP154,526, MTIP had a markedly reduced volume of distribution and clearance. Neither open field activity nor baseline exploration of an elevated plus-maze was affected by MTIP (1–10mg/kg). In contrast, MTIP dose-dependently reversed anxiogenic effects of withdrawal from a 3 g/kg alcohol dose. Similarly, MTIP blocked excessive alcohol self-administration in Wistar rats with a history of dependence, and in a genetic model of high alcohol preference, the Marchigian Sardinian (msP) rat, at doses that had no effect
