In vitro and in vivo profiling of fadolmidine, a novel potent α2-adrenoceptor agonist with local mode of action

Abstract Alpha2-adrenergic receptors (α2-adrenoceptors) mediate various physiological actions of endogenous catecholamines in the central and peripheral nervous systems being involved in alertness, heart rate regulation, vasomotor control and nociceptive processing. In the present study, the pharmacological profile of a novel α2-adrenoceptor agonist, fadolmidine, was studied in various in vitro and in vivo assays and compared to the well characterised α2-adrenoceptor agonist, dexmedetomidine. Fadolmidine displayed high affinity and full agonist efficacy at all three human α2-adrenoceptor subtypes (A, B and C) in transfected CHO cells with EC50 values (nM) of 0.4, 4.9 and 0.5, respectively. Fadolmidine inhibited also electrically evoked contractions in rat vas deferens demonstrating the activation of rodent presynaptic α2D-adrenoceptors with an EC50 value of 6.4 nM. Moreover, fadolmidine was a full agonist at human α1A-adrenoreceptor (EC50 value 22 nM) and α1B-adrenoreceptor (EC50 value 3.4 nM) in human LNCaP cells and transfected HEK cells, respectively. Agonism at the α1-adrenoceptor was also observed in rat vas deferens preparations although at lower potency (EC50 value 5.6 μM). Fadolmidine demonstrated potent α2-adrenoceptor agonist activity also in vivo by inhibiting electrically induced tachycardia in pithed rats and increasing mean arterial pressure in anaesthetised rats. However, after systemic administration, fadolmidine had considerably weaker CNS-mediated effects (mydriasis and sedation) compared to dexmedetomidine possibly due to limited penetration through the blood brain barrier by fadolmidine. In a conclusion, fadolmidine is a potent full agonist at all three α2-adrenoceptor subtypes with a pharmacological profile compatible with a therapeutic value e.g. after spinal administration.