Synthesis and anticonvulsant properties of tetrahydroisoquinoline derivatives Rosaria Gitto a, *, Roberta Caruso a , Valerie Orlando a , Silvana Quartarone a , Maria Letizia Barreca a , Guido Ferreri b , Emilio Russo b , Giovambattista De Sarro b , Alba Chimirri a a Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, Messina 98168, Italy b Dipartimento di Medicina Sperimentale e Clinica, Università “Magna Græcia” di Catanzaro, Via T. Campanella, 88100, Italy Received 24 July 2003; accepted 24 October 2003 Abstract As a follow up of our previous structure–activity relationship and molecular modeling studies, we synthesized a novel series of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as potential non-competitive AMPA receptor antagonists. When tested for their ability to prevent sound-induced seizures in DBA/2 mice, some of these novel compounds showed high anticonvulsant potency. © 2003 Elsevier SAS. All rights reserved. Keywords: AMPA receptor antagonists;Anticonvulsant agents; Tetrahydroisoquinolines; DBA/2 mice 1. Introduction The excitatory neurotransmitter glutamate binds both me- tabotropic (mGluRs) and ionotropic receptors (iGluRs) and controls many fundamental processes. Ion channels repre- sent important pharmacological targets for drug intervention and treatment of disorders in the central nervous system (CNS). Molecules that modulate ion channel activities have been actively investigated as potential drugs for the treatment of depression and anxiety, impairments in cognition and memory, epilepsy and neuronal ischemia. [1–4]. In particular, it is well known that 2-amino-3-(3-hydroxy- methylisoxazol-4-yl)propionic acid (AMPA) receptor (AM- PAR) type of iGluRs plays a role in epileptogenesis and several AMPAR antagonists show promise in terms of their therapeutic potential for the prevention and treatment of epilepsy [5–8]. In fact, a selective and non-competitive blockade of AMPA receptor was shown by some 2,3-benzo- diazepines [9–12], such as the 1-(4-aminophenyl)-4-methyl- 7,8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466) (Chart 1) and in particular the (R)-7-acetyl-5-(p- aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h] [2,3]benzodiazepine (2, talampanel), which possesses potent anticonvulsant properties and which is being submitted to phase II clinical trial [13]. In our previous studies [14–24], we identified other 2,3- benzodiazepine derivatives, such as 1-(4-aminophenyl)-3,5- dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one (3, CFM-2) [14], thiocarbonyl analog 4 (CFM-2S) [17] and 8,9-dimethoxy-6-(4-bromophenyl)-11H-[1,2,4]triazolo[4,5- c][2,3]benzodiazepin-3(2H)-one [23] (5) (Chart 1) that showed marked antiepileptic properties in various animal models of convulsive epilepsy. Electrophysiological studies confirmed that their anticonvulsant effects are mediated through the AMPAR allosteric modulation. We have recently developed [25] a pharmacophore 3D- model of non-competitive AMPAR antagonists and found that compounds containing 6,7-dimethoxy-1,2,3,4-tetra- hydroisoquinoline skeleton satisfied the pharmacophore hy- pothesis. The synthesis of a series of these derivatives was carried out and the obtained compounds were tested for their anticonvulsant properties [26]. The pharmacological screen- ing put in evidence that some synthesized compounds proved to be anticonvulsant agents acting as new non-competitive AMPAR antagonists. In particular, the 2-acetyl-1-(4-chloro- phenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 6c (Chart 1) was characterized in vivo and in vitro tests by an * Corresponding author. E-mail address: rgitto@pharma.unime.it (R. Gitto). IL FARMACO 59 (2004) 7–12 www.elsevier.com/locate/farmac © 2003 Elsevier SAS. All rights reserved. doi:10.1016/j.farmac.2003.10.003