title: Assessment of binding affinity to 5-hydroxytryptamine 2A (5-HT2A) receptor and inverse agonist activity of naftidrofuryl: comparison with those of sarpogrelate.
abstract: Naftidrofuryl is a peripheral vasodilator that has been clinically used in the treatment of intermittent claudication and dementia. It has 5-hydroxytryptamine 2 (5-HT(2)) antiserotonergic activity and selectively binds with the 5-HT(2) receptor. The purpose of the present study is to assess the binding affinity and functional potency of naftidrofuryl to the 5-HT(2A) receptor, to find out the inverse agonist activity of this compound at a constitutively active mutant of 5-HT(2A) receptor, and finally to compare the findings with those of sarpogrelate. The investigation showed that the binding affinity (pK(i)) of naftidrofuryl was decreased 25- or 50-fold compared to sarpogrelate in the wild-type 5-HT(2A) receptor or Cys322Lys mutant receptor, respectively. Moreover, the functional potency (pK(b)) of naftidrofuryl was much lower compared to sarpogrelate at the 5-HT(2A) receptor. In addition, inverse agonist activity of naftidrofuryl was lower compared with sarpogrelate at the constitutively active mutant receptor. Thus, the data of the present study would be very important for the clarification of interaction sites of naftidrofuryl to 5-HT(2A) receptors and also may help to understand the mechanism of inverse agonist activity at the constitutively active mutant receptor.
authors: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
authors: Saida Abdel Regal
authors: SA
authors: Aly
authors: Murad
authors: M
authors: Hossain
authors: Mohiuddin Ahmed
authors: MA
authors: Bhuiyan
authors: Takashi
authors: T
authors: Nakamura
authors: Takafumi
authors: T
authors: Nagatomo
mesh_terms: D002460:Cell Line; D054314:Drug Inverse Agonism; D006801:Humans; D009154:Mutation; D009257:Nafronyl / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000378:metabolism*; D013386:Succinates / Q000378:metabolism*; D014665:Vasodilator Agents / Q000378:metabolism
chemical_list: D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D013386:Succinates; D014665:Vasodilator Agents; C064294:sarpogrelate; D009257:Nafronyl