IFENPRODIL INHIBITION OF THE 5-HYDROXYTRYPTAMINE(3) RECEPTOR

The anti-hypertensive drug ifenprodil is known to interact potently wi th the alpha(1)-adrenergic receptor as well as a number of other secon d messenger-linked receptors. In addition to these properties, ifenpro dil has been shown to prevent glutamate-mediated excitotoxcity via non -competitive antagonism of NMDA receptors [Legendre and Westbrook (199 1) Molec. Pharmac. 40: 289-298; Shalaby et al. (1992) J. Pharmac. Exp. Ther. 260: 925-932]. With these things in mind, we have begun to exam ine the specificity of ifenprodil for various ligand-gated ion channel s using electrophysiological methods. While ifenprodil effectively inh ibits NMDA-mediated currents in cortical neurons in culture, it does n ot interact with either kainate or GABA receptors. Surprisingly, ifenp rodil also, acts as a relatively potent antagonist of the 5-hydroxytry ptamine(3) (5-HT3) receptor in the NG108-15 neuroblastoma x glioma cel l line. Furthermore, several aspects of ifenprodil action on the 5-HT3 receptor resemble its interaction with the NMDA receptor. Namely, inh ibition of 5-HT3-mediated cation currents is readily reversible, has r elatively slow onset, is non-competitive, and is not voltage dependent . Since most of the known 5-HT3 antagonists are competitive, it is pos sible that ifenprodil may define a unique modulatory site(s) on this n eurotransmitter receptor.