title: A pharmacophore derived phenytoin analogue with increased affinity for slow inactivated sodium channels exhibits a desired anticonvulsant profile.
abstract: Phenytoin (DPH) is a clinically useful sodium (Na) channel blocker with efficacy against partial and generalized seizures. We have developed a novel hydantoin compound (HA) using comparative molecular field analysis (CoMFA) and evaluated its effects on hNa(v)1.2 channels. Both DPH and HA demonstrated affinity for resting (K(r)=13.9microM for HA, K(r)=464microM for DPH) and slow inactivated channels (K(I)=975nM for HA, K(I)=20.6microM for DPH). However, HA also exhibited an affinity for fast inactivated channels (K(I)=2.5microM) and shifted the V(1/2) for activation in the depolarizing direction. Furthermore, HA exhibited profound use dependent block at both 5 and 10Hz stimulation frequencies. In the 6Hz seizure model (32mA) HA had an ED(50) of 47.1mg/kg and a TD(50) of 131mg/kg (protective index (PI)=2.8). In comparison, the ED(50) for DPH was approximately 27.5mg/kg with a TD(50) of 35.6mg/kg (PI approximately 1.3). These findings provide evidence for the utility of CoMFA in the design of novel anticonvulsants and support the hypothesis that states selectivity plays an important role in achieving optimal protection with minimal side effects.
authors.affiliation: Department of Anesthesiology, University of Virginia Health System, 1 Hospital Drive, Box 800710, Charlottesville, VA 22908-0710, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Lenkowski
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Batts
authors.forename: Misty D
authors.initials: MD
authors.lastname: Smith
authors.forename: Seong-Hoon
authors.initials: SH
authors.lastname: Ko
authors.forename: Paulianda J
authors.initials: PJ
authors.lastname: Jones
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Taylor
authors.forename: Ashley K
authors.initials: AK
authors.lastname: McCusker
authors.forename: Gary C
authors.initials: GC
authors.lastname: Davis
authors.forename: Hali A
authors.initials: HA
authors.lastname: Hartmann
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Patel
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004341:Drug Evaluation; D004558:Electric Stimulation / Q000379:methods; D006801:Humans; D006827:Hydantoins / Q000737:chemistry / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D018408:Patch-Clamp Techniques / Q000379:methods; D010672:Phenytoin / Q000737:chemistry / Q000494:pharmacology*; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology; D014162:Transfection / Q000379:methods
chemical_list: D000927:Anticonvulsants; D006827:Hydantoins; D015222:Sodium Channels; D010672:Phenytoin