Ifenprodil inhibition of the 5-hydroxytryptamine3 receptor.
The anti-hypertensive drug ifenprodil is known to interact potently with the alpha 1-adrenergic receptor as well as a number of other second messenger-linked receptors. In addition to these properties, ifenprodil has been shown to prevent glutamate-mediated excitotoxicity via non-competitive antagonism of NMDA receptors [Legendre and Westbrook (1991) 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 examine the specificity of ifenprodil for various ligand-gated ion channels using electrophysiological methods. While ifenprodil effectively inhibits NMDA-mediated currents in cortical neurons in culture, it does not interact with either kainate or GABA receptors. Surprisingly, ifenprodil also acts as a relatively potent antagonist of the 5-hydroxytryptamine3 (5-HT3) receptor in the NG108-15 neuroblastoma x glioma cell line. Furthermore, several aspects of ifenprodil action on the 5-HT3 receptor resemble its interaction with the NMDA receptor. Namely, inhibition of 5-HT3-mediated cation currents is readily reversible, has relatively slow onset, is non-competitive, and is not voltage dependent. Since most of the known 5-HT3 antagonists are competitive, it is possible that ifenprodil may define a unique modulatory site(s) on this neurotransmitter receptor.
McCool
B A
BA
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232-0615, USA.
Lovinger
D M
DM
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D007608:Kainic Acid / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology*; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D010880:Piperidines; D011985:Receptors, Serotonin; D014665:Vasodilator Agents; D012701:Serotonin; D005680:gamma-Aminobutyric Acid; C010739:ifenprodil; D007608:Kainic Acid