Pharmacological characterization of FE 201874, the first selective high affinity rat V 1A vasopressin receptor agonist

Background and Purpose Distinct vasopressin receptors are involved in different physiological and behavioural functions. Presently, no selective agonist is available to specifically elucidate the functional roles of the V 1A receptor in the rat, one of the most widely used animal models. FE 201874 is a new derivative of the human selective V 1A receptor agonist F180 . In this study, we performed a multi‐approach pharmacological and functional characterization of FE 201874 to determine whether it is selective for V 1A receptors. Experimental Approach We modified an available human selective V 1A receptor agonist ( F180 ) and determined its pharmacological properties in cell lines expressing vasopressin/oxytocin receptors (affinity and coupling to second messenger cascades), in an ex vivo model (aorta ring contraction) and in vivo in rats (proliferation of adrenal cortex glomerulosa cells and lactation). Key Results FE 201874 exhibited nanomolar affinity for the rat V 1A receptor; it was highly selective towards the rat V 1B and V 2 vasopressin receptors and behaved as a full V 1A agonist in all the pharmacological tests performed. FE 201874 bound to the oxytocin receptor, but with moderate affinity, and behaved as an oxytocin antagonist in vitro, but not in vivo . Conclusions and Implications On functional grounds, all the data demonstrate that FE 201874 is the first selective agonist of the rat V 1A receptor isoform available. Hence, FE 201874 may have potential as a treatment for the vasodilator‐induced hypotension occurring in conditions such as septic shock and could be the most suitable compound for discriminating between the behavioural effects of arginine vasopressin and oxytocin.