Anthes John C, Gilchrest Helen, Richard Christian, Eckel Stephen, Hesk Dave, West Robert E, Williams Shirley M, Greenfeder Scott, Billah Motasim, Kreutner William, Egan Robert E
Schering-Plough Research Institute, K15-1-1600, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA.
Eur J Pharmacol. 2002 Aug 9;449(3):229-37. doi: 10.1016/s0014-2999(02)02049-6.
We have characterized desloratadine (5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 8-chloro-6,11-dihydro-11-(4-piperidinylidene), CAS 100643-71-8) as a potent antagonist of the human histamine H(1) receptor. [3H]Desloratadine bound to membranes expressing the recombinant human histamine H(1) receptor in Chinese hamster ovary cells (CHO-H(1)) in a specific and saturable manner with a K(d) of 1.1+/-0.2 nM, a B(max) of 7.9+/-2.0 pmol/mg protein, and an association rate constant of 0.011 nM(-1) x min(-1). The K(d) calculated from the kinetic measurements was 1.5 nM. Dissociation of [3H]desloratadine from the human histamine H(1) receptor was slow, with only 37% of the binding reversed at 6 h in the presence of 5 microM unlabeled desloratadine. Seventeen histamine H(1)-receptor antagonists were evaluated in competition-binding studies. Desloratadine had a K(i) of 0.9+/-0.1 nM in these competition studies. In CHO-H(1) cells, histamine stimulation resulted in a concentration-dependent increase in Ca(2+) with an EC(50) of 170+/-30 nM. After a 90-min preincubation with desloratadine, the histamine-stimulated increase in Ca(2+) was shifted to the right, with a depression of the maximal response at higher concentrations of antagonist. The apparent K(b) value was 0.2+/-0.14 nM with a slope of 1.6+/-0.1. The slow dissociation from the receptor and noncompetitive antagonism suggests that desloratadine may be a pseudoirreversible antagonist of the human histamine H(1) receptor. The mechanism of desloratadine antagonism of the human histamine H(1) receptor may help to explain the high potency and 24-h duration of action observed in clinical studies.
我们已将地氯雷他定（5H-苯并[5,6]环庚并[1,2-b]吡啶，8-氯-6,11-二氢-11-(4-哌啶亚基)，CAS 100643-71-8）鉴定为人组胺H(1)受体的强效拮抗剂。[3H]地氯雷他定以特异性和可饱和的方式与表达重组人组胺H(1)受体的中国仓鼠卵巢细胞（CHO-H(1)）膜结合，解离常数（K(d)）为1.1±0.2 nM，最大结合容量（B(max)）为7.9±2.0 pmol/mg蛋白，结合速率常数为0.011 nM(-1)·min(-1)。根据动力学测量计算得到的K(d)为1.5 nM。[3H]地氯雷他定从人组胺H(1)受体上的解离较慢，在存在5 μM未标记地氯雷他定的情况下，6小时时仅有37%的结合被逆转。在竞争结合研究中评估了17种组胺H(1)受体拮抗剂。在这些竞争研究中，地氯雷他定的抑制常数（K(i)）为0.9±0.1 nM。在CHO-H(1)细胞中，组胺刺激导致细胞内钙离子浓度（Ca(2+)）呈浓度依赖性增加，半数有效浓度（EC(50)）为170±30 nM。用地氯雷他定预孵育90分钟后，组胺刺激引起的Ca(2+)增加向右移动，在较高浓度拮抗剂时最大反应降低。表观平衡解离常数（K(b)）值为0.2±0.14 nM，斜率为1.6±0.1。从受体上的缓慢解离和非竞争性拮抗作用表明，地氯雷他定可能是人组胺H(1)受体的拟不可逆拮抗剂。地氯雷他定拮抗人组胺H(1)受体的机制可能有助于解释临床研究中观察到的高效能和24小时的作用持续时间。
