Biochemical characterization of desloratadine, a potent antagonist of the human histamine H1 receptor

Ligand Residence Time at G-protein–Coupled Receptors—Why We Should Take Our Time To Study It

“…The first generation antagonist mepyramine (pyrilamine) competitively antagonizes histamine-induced increase in intracellular [Ca 21 ] and guinea pig ileum contraction, resulting in a right shift of the histamine concentration response curves without affecting the maximal response (Anthes et al, 2002;Slack et al, 2011b). In contrast, other antihistamines such as azelastine, desloratidine (Aerius; Merck Sharp & Dohme, Whitehouse Station, NJ),…”

“…, and ceterizine (Zyrtec; UCB, Brussels, Belgium) inhibited histamine-induced Ca 21 signaling and/or smooth muscle cell contraction in an apparently noncompetitive manner, resulting in an attenuated maximal response (Anthes et al, 2002;Slack et al, 2011a,b). Indeed, these insurmountable antagonists dissociated at least 70-fold more slowly from the H 1 R compared with mepyramine (Gillard et al, 2002;Anthes et al, 2002;Gillard and Chatelain, 2006;Slack et al, 2011b).…”

“…Indeed, these insurmountable antagonists dissociated at least 70-fold more slowly from the H 1 R compared with mepyramine (Gillard et al, 2002;Anthes et al, 2002;Gillard and Chatelain, 2006;Slack et al, 2011b).…”

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…After administration of ebastine, carebastine concentrations are 30-fold greater (Sastre, 2008;Shon et al, 2010). Furthermore, carebastine is intrinsically more potent at the H 1 receptor (Anthes et al, 2002). The exact values for plasma protein binding have not been reported as both parent and metabolite are highly bound and merely reported as .95%.…”

“…20). The intrinsic potency of desloratadine far exceeds that of the parent (Anthes et al, 2002), the free fraction is higher by 5-fold, and the circulating concentrations are also higher (Ramanathan et al, 2007). When these three factors are combined, it suggests that loratadine itself is responsible for none of the in vivo antihistaminic activity.…”