Rational Drug Design and the Discovery of the Δ2-1,2,3-Triazolines, A Unique Class of Anticonvulsant and Antiischemic Agents

Abstract

The delta(2)- 1,2,3- triazoline anticonvulsants (TRs) may be considered as representing a unique class of "built-in" heterocyclic prodrugs where the active "structure element" is an integral part of the ring system and can be identified only by a knowledge of their chemical reactivity and metabolism. Investigations on the metabolism and pharmacology of a lead triazoline, ADD17014 suggest that the triazolines function as "prodrugs" and exert their anticonvulsant activity by impairing excitatory amino acid (EAA) L-Glutamate (L-Glu) neurotransmission via a unique "dual-action" mechanism. While an active primary beta-amino alcohol metabolite from the parent prodrug acts as an N-methyl-D-aspartate (NMDA)/MK -801 receptor antagonist, the parent triazoline impairs the presynaptic release of L-Glu. Various pieces of theoretical reasoning and experimental evidence have led to the clucidation of the dual-action mechanism. Based on the unique chemistry of the triazolines, and their metabolic pathways, biotransformation products of TRs were predicted to be the beta-amino alcohols V and VA, the alpha-amino acid VI, the triazole VII, the aziridine VIII and the ketimine IX. In vivo and in vitro pharmacological studies of the TR and potential metabolites, along with a full quantitative urinary metabolic profiling of TR indicated the primary beta-amino alcohol V as the active species. It was the only compound that inhibited the specific binding of [3H]MK-801 to the MK-801 site, 56% at 10 micro M drug concentration, but itself had no anticonvulsant activity, suggesting TR acted as a prodrug. Three metabolites were identified; V was the most predominant (45.7 +/- 7.6) % of administered drug, with lesser amounts of VA, (17.3 +/- 5.1) % and very minor amounts of aziridine VIII (4.0 +/- 0.02)%. Since only VIII can yield VA, its formation indicated that the biotransformation of TR occurred, at least in part, through aziridine. No amino acid metabolite was detected, which implied that no in vivo oxidation of V or oxidative biotransformation of TR or aziridine by hydroxylation at the methylene group occurred. While triazoline significantly decreased Ca(2+) -dependent, k(+)-evoked L-Glu release (83% at 100 micro M drug concentration ), some triazolines showed an augmentation of 50-63%, in the Cl(-) channel activity, a useful membrane action that reduces the excessive L-Glu release that occurs during epileptic seizures. The high anticonvulsant activity of TRs in a variety of seizure models including their effectiveness in the kindling model of complex partial seizures may be due to their unique dual-action mechanism whereby the TR and V together effectively impair both pre- and postsynaptic aspects of EAA neurotransmission; thus the TRs have clinical potential in the treatment of complex partial epilepsy which is refractory to currently available drugs. Since there is strong evidence that L-Glu plays an important role in human epilepsy as well as in brain ischemia/stroke, and since the TRs act by inhibiting EAA neurotransmission, it was lo...

Synthesis and Anticonvulsant Activity of 1-Substituted-7-Benzyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline

“…Based on previous reports, [12][13][14] we knew that trazoles have activity against both major and minor seizures. The MES test is regarded as the pharmacologic model of grand mal, and the sc-Met test as the pharmacologic model of petit mal seizures.…”

“…[12][13][14] In our search for new compounds with anticonvulsant activity, 6-benzyloxy-3,4-dihydro-1H-quinoline-2-one was found although its activity is low. To increase its anticonvulsant activity and taking into account the anticonvulsant activity of triazole, we incorporated triazole with 6-benzyloxy-3,4-dihydro-1H-quinolinone at the first and second position of the latter and obtained 7-benzyloxy-4,5-dihydro- [1,2,4]triazolo [4,3-a]quinoline with more potent activity.…”

Multifunctional drugs with different CNS targets for neuropsychiatric disorders

“…The Δ 2 ‐1,2,3‐triazoline anti‐convulsant, ADD17014 (Fig. 2: 17), has been shown to modulate excitatory amino acid neurotransmission through a unique dual mechanism (Kadaba 2003). The parent pro‐drug triazoline compound, ADD17014, attenuates presynaptic glutamate release (83% at 100 µ m ), while its β‐amino‐alcohol metabolite (see Fig.…”

Novel Multifunctional Anti-Alzheimer Drugs with Various CNS Neurotransmitter Targets and Neuroprotective Moieties

“…The 2 -1,2,3-triazoline anticonvulsant ADD17014 ( Table 5) has been shown to modulate excitatory amino acid neurotransmission through a unique dual mechanism [97]. Its parent triazoline pro-drug compound attenuates presynaptic glutamate release (83% at 100 μM), while its -amino-alcohol metabolite ( Table 5) acts as an NMDA receptor antagonist by binding to the MK-801 site (56% at 10 μM), located inside the NMDA receptor/ion channel.…”