Published: April 11, 2011 r2011 American Chemical Society 317 dx.doi.org/10.1021/cn200024z | ACS Chem. Neurosci. 2011, 2, 317–332 RESEARCH ARTICLE pubs.acs.org/acschemicalneuroscience Merging Structural Motifs of Functionalized Amino Acids and r-Aminoamides Results in Novel Anticonvulsant Compounds with Significant Effects on Slow and Fast Inactivation of Voltage-Gated Sodium Channels and in the Treatment of Neuropathic Pain Yuying Wang, † Sarah M. Wilson, #,§ Joel M. Brittain, #,§ Matthew S. Ripsch, ‡,§ Christophe Salom e, ^ Ki Duk Park, ^ Fletcher A. White, ‡,§ Rajesh Khanna,* ,†,§ and Harold Kohn* ,||,^ † Department Pharmacology and Toxicology, ‡ Department of Anesthesia, and § Program in Medical Neuroscience, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States ) Department of Chemistry and ^ Division of Medicinal Chemistry and Natural Products, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States R ecently, we reported a novel series of neurological com- pounds 1 that merged key pharmacophores found in two classes of clinical neurological agents, functionalized amino acids (FAAs, 2) 210 and R-amino acid amides (AAAs, 3), 1115 into the concise structure 1 (Figure 1). Lacosamide 10 (Vimpat, (R)-4) is the prototypical FAA and is a first-in-class antiepileptic drug (AED) that is marketed in the United States and Europe for adjunctive treatment of partial onset seizures in adults. 16 Safina- mide ((S)-5) and ralfinamide ((S)-6) are representative AAAs, and both have undergone extensive clinical trials. 1115 While (S)-5 12,13 and (S)-6 14,15 are potent anticonvulsants, Merck- Sorono has advanced (S)-5 for the treatment of Parkinson’s disorders, and Newron has evaluated (S)-6 for neuropathic lower back pain. Recent, late-stage human clinical trials have indicated that neither (S)-5 nor (S)-6 met their clinical end points, although they exhibited no undesirable side effects. 17,18 At first glance, 2 and 3 appear similar in structure due to the vicinal diamine backbone that contains a carbonyl (CdO) moiety, the presence of one chiral center, and the inclusion of a N-benzyl (PhCH 2 )-type substituent. Pharmacologically, (R)-4, (S)-5, and (S)-6 exhibited excellent seizure protection 10,19,20 in the maximal electroshock seizure (MES) animal model, 21 and electrophysiology studies demonstrated that these agents modu- lated sodium currents. 13,15,22,23 However, (R)-4 selectively Received: March 11, 2011 Accepted: April 11, 2011 ABSTRACT: We recently reported that merging key structural pharmacophores of the anticonvulsant drugs lacosamide (a functionalized amino acid) with safinamide (an R-aminoamide) resulted in novel compounds with anticonvulsant activities superior to that of either drug alone. Here, we examined the effects of six such chimeric compounds on Na þ -channel func- tion in central nervous system catecholaminergic (CAD) cells. Using whole-cell patch clamp electrophysiology, we demon- strated that these compounds affected Na þ channel fast and slow inactivation processes. Detailed electrophysiological char- acterization of two of these chimeric compounds that contained either an oxymethylene ((R)-7) or a chemical bond ((R)-11) between the two aromatic rings showed comparable effects on slow inactivation, use-dependence of block, development of slow inactivation, and recovery of Na þ channels from inactiva- tion. Both compounds were equally effective at inducing slow inactivation; (R)-7 shifted the fast inactivation curve in the hyperpolarizing direction greater than (R)-11, suggesting that in the presence of (R)-7 a larger fraction of the channels are in an inactivated state. None of the chimeric compounds affected veratridine- or KCl-induced glutamate release in neonatal cortical neurons. There was modest inhibition of KCl-induced calcium influx in cortical neurons. Finally, a single intraperitoneal administration of (R)-7, but not (R)-11, completely reversed mechanical hypersensitivity in a tibial-nerve injury model of neuropathic pain. The strong effects of (R)-7 on slow and fast inactivation of Na þ channels may contribute to its efficacy and provide a promising novel therapy for neuropathic pain, in addition to its antiepileptic potential. KEYWORDS: Lacosamide, safinamide, sodium channel, slow/fast inactivation, state-dependent, neuropathic pain