Novel potent AMPA/kainate receptor antagonists: synthesis and anticonvulsant activity of a series of 2-[(4-alkylsemicarbazono)-(4-amino-phenyl)methyl]-4,5-methylenedioxyphenylacetic acid alkyl esters.
In this paper we describe the synthesis of a series of novel 2-[(4-alkylsemicarbazono)-(4-aminophenyl)-methyl]-4,5-methylenedioxyphenylacetic acid alkyl esters (10-19) carrying an alkylsemicarbazono moiety at a benzylic site. The influence of this group on the biological activity was evaluated by testing the corresponding derivatives 20-22 in which the 4-alkylsemicarbazono moiety was removed (compound 20) or its alkylureido portion shifted at position 1 (compounds 21-22). Furthermore, the involvement of the 4-aminobenzyl moiety in the anticonvulsant activity was evaluated by testing derivative 23. The anticonvulsant activity of all compounds was assayed against audiogenic seizures induced in DBA/2 mice. Within this series of derivatives, 2-[(4-aminophenyl)-(4-methylsemicarbazono)-methyl]-4,5-methylenedioxyphenylacetic acid methyl ester (10) proved to be the most active compound. It displayed a potency 5-fold higher than that shown by 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), a well-known noncompetitive 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptor antagonist. Compound 10 was also effective in suppressing seizures induced in Swiss mice by maximal electroshock (MES) or pentylenetetrazole (PTZ). Furthermore, it antagonized in vivo seizures induced by icv administration of AMPA or kainate (KA). Using the patch-clamp technique in primary cultures of granule neurons we tested compounds 10 and 21 for their ability to modulate currents evoked by KA and 2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propionic acid (ATPA). These two derivatives reduced KA and ATPA currents to a larger extent than that shown by reference compound 1. Compounds 10 and 21 were also able to reduce neuronal cell death induced by the application of KA (100 microM).
Micale
Nicola
N
Dipartimento Farmaco-Chimico, Università di Messina, Italy.
Zappalà
Maria
M
Grasso
Silvana
S
Puja
Giulia
G
De Sarro
Giovambattista
G
Ferreri
Guido
G
De Sarro
Angela
A
Toma
Lucio
L
De Micheli
Carlo
C
D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002531:Cerebellum / Q000166:cytology; D004149:Dioxoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors; D012640:Seizures / Q000209:etiology / Q000517:prevention & control; D012664:Semicarbazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D004149:Dioxoles; D018691:Excitatory Amino Acid Antagonists; D007555:Isoxazoles; D007608:Kainic Acid; D010648:Phenylacetates; D011422:Propionates; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D012664:Semicarbazones; C466638:2-((4-aminophenyl)-(4-methylsemicarbazono)methyl)-4,5-methylenedioxyphenylacetic acid methyl ester; C081662:alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionate