Synthesis and Structure-Active Relationship of 1-Aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Anticonvulsants

Abstract

Epilepsy is commonly considered the result of an imbalance between excitatory and inhibitory "tone" leading to periodic and unpredictable seizures related to an abnormal discharge of cerebral neurons. Epilepsy is one of the most common neurological disorders, affecting ca. 1% of the population worldwide, and the incidence increases to 3% by the age of 75 years. Although most people become seizure-free with drug therapy, there is still a significant number of patients (30%) who are resistant to the currently available antiepileptic drugs whether used alone or in combination. The pathophysiology of epilepsy is complex and several mechanisms play a role in epileptogenesis and epileptogenicity.1) The efficacy of anticonvulsant drugs may be connected with different molecular targets to reduce the excitability of neurons involved in seizure onset.2) The mechanism of action of currently available effective antiepileptics are: a) the induction of a prolonged inactivation of the Na ϩ channel; b) the blockade of Ca 2ϩ channel currents; c) the enhancement of the inhibitory g-aminobutyrate (GABA)ergic neurotransmission or the modulation of excitatory glutamatergic neurotransmission.3) With respect to this last pharmacological target, extensive studies have demonstrated that competitive and noncompetitive antagonists of the ionotropic glutamate receptors (iGluRs) show promise in terms of their therapeutic potential for the prevention and treatment of the epilepsy. [3][4][5][6][7][8][9][10] In our previous works, some isoquinoline derivatives were found to have anticonvulsant activities in various seizure models interacting with glutamate ionotropic a-amino-3-hydroxyl-5-methyl-4-isoxazole propionate (AMPA) receptor (AMPAR) subtype in a selective and non-competitive fashion. [11][12][13][14][15][16][17][18][19][20] The most active compound of the series was the 2-acetyl-1-(4Ј-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (1, Fig. 1) which showed both in in vivo and in vitro tests activity stronger than other known AMPAR antagonists such as GYKI 52466, talampanel, and CFM-2 (Fig. 1). 17,21,22) Starting from the "lead compound" 1, in several previous studies, we examined a large series of its analogues and reported a comprehensive structure-active relationship (SAR) studies concerning the influence of specific substituents on tetrahydroisoquinoline skeleton; we found that the most active derivatives are generally characterized by the presence of 2-acetyl substituent; moreover two methoxy substituents on the benzene fused ring are crucial to produce pharmacological effects.19) Furthermore our investigations suggested that the introduction of hydrophobic substituents at 4Ј-position of C-1 phenyl moiety (e.g. halogen atoms) could improve the anticonvulsant efficacy against sound-induced seizures in Dilute Brown non-Agouti (DBA/2) mice. These experimental evidences were confirmed by our computational studies in which we developed a 3-D pharmacophore model for noncompetitive AMPAR antagonists.15) Herein we report the sy...

Novel angularly substituted [1,4]thiazino[3,4‐a]isoquinoline carboxylic acids prepared by cyclic imine‐cyclic anhydride reaction

“…Furthermore, the expected products would incorporate an 1‐aryl‐tetrahydroisoquinoline moiety, found in compounds with anti‐HIV, [ 5 ] antimalarial [ 6 ] and anticonvulsant activity. [ 7 ]…”

The formation of the salt and neutral molecule cocrystal from equimolar solution of heliamine and bicyclo[2.2.1]hept-5-ene-endo-2,3-dicarboxylic acid

“…Heliamine is found in some Mexican cacti (Backebergia militaris, Carnegiea gigantea, Pachycereus pecten-aboriginum, Pachycereus pringlei, Pachycereus weberi) (Strombö m & Bruhn, 1978a,b;Mata & McLaughlin, 1980;Pummangura et al, 1982;Menachery et al, 1986) and exhibits strong anticancer action as an inhibitor of rat sarcoma (Strombö m & Bruhn, 1978a,b). Some derivatives of tetrahydroisoquinoline possess anticancer (Patil et al, 2014), antidiabetic (Song et al, 2014), antidepressant (Możdżeń et al, 2014;Antkiewicz-Michaluk et al, 2014a,b;Wąsik et al, 2014) and anticonvulsant (Gitto et al, 2010) action and also have contractile activity against guinea pig's gastric smooth muscle preparations (Ivanov et al, 2011). In addition, heliamines substituted by hydroxyl or carboxyl groups were shown to be low-molecular-weight hydrogelators (Kang et al, 2011(Kang et al, , 2014Xu et al, 2012) which are useful in catalytical and biological applications (Tian et al, 2014;Dö ring et al, 2013;Xu, 2009;Estroff & Hamilton, 2004).…”

Looking toward the Rim of the Active Site Cavity of Druggable Human Carbonic Anhydrase Isoforms

“…In this context, the benzenesulfonamide moiety has been extensively explored as a crucial binding motif for the CA active site cavity close to the zinc ion . To improve the isoform selectivity of CAIs, efforts have been generally addressed to introduce an additional fragment linked to benzenesulfonamide as a “tail” for enhancing the interaction with hydrophobic/hydrophilic residues paving the middle and/or top region of the active site cavity. ,,,− …”