CRL41405: a drug with a new pharmacological profile on pancreatic exocrine secretion in the rat

The recently described compound CRL41405 displays central effects suggesting possible antidepressive and awakening properties. In order to further analyze the pharmacology of this compound, its effects were studied on basal and stimulated pancreatic secretion in anaesthetized rats. CRL41405 alone (7-20 mg/kg, sc) had no effect on basal pancreatic secretion. Larger doses (67-200 mg/kg) increased basal secretion through the stimulation of cholinergic muscarinic receptors, the effect being antagonized by atropine. CRL41405 (20 mg/kg) suppressed the 2-deoxyglucose-induced (but not the acetylcholine-induced) stimulation of pancreatic secretion through an alpha-2 adrenoceptor inhibitory mechanism that was blocked by idazoxan (0.3 mg/kg, sc). In addition, a beta adrenoceptor mediated stimulation of sodium and bicarbonate excretion (blocked by propranolol) was evidenced when the alpha-2 inhibition was suppressed by idazoxan. Under alpha-2 adrenoceptor blockade, water and electrolyte stimulation by CRL41405 could be demonstrated on basal, 2-deoxyglucose-induced and acetylcholine-induced pancreatic secretion. This original profile makes CRL41405 a unique drug in pancreatic pharmacology.