Novel secoergoline derivatives inhibit both GABA and glutamate uptake in rat brain homogenates: synthesis, in vitro pharmacology, and modeling.
Three of twelve secoergoline derivatives (Z ethyl 4-[(ethoxycarbonylmethyl)methylamino]-2-methyl-3-phenylpent-2-enoate, 8; ethyl 1,6-dimethyl-3-oxo-5-phenyl-1,2,3,6-tetrahydropyridine-2-carboxylate, 9; Z methyl 4-[(methoxycarbonylmethyl)methylamino)-2-methyl-3-phenylpent-2-enoate, 11), containing bioisosteric sequences of GABA and Glu, inhibited both GABA and Glu transport through cerebrocortical membranes specifically. Compounds 8, 9, and 11 appeared to be equipotent inhibitors of GABA and Glu transport with IC50 values between 270 and 1100 microM, whereas derivatives 1-7, 10, and 12 were without effects. In the presence of GABA and Glu transport-specific nontransportable inhibitors, inhibition of GABA and Glu transport by 8, 9, and 11 proceeded in two phases. The two phases of inhibition were characterized by IC50 values between 4 and 180 nM and 360-1020 microM and different selectivity sequences. These findings may indicate the existence of some mechanism possibly mediated by a previously unrecognized GABA-Glu transporter. Derivatives with the cis, but not the trans configuration of bulky ester groups (8 vs 7 and 11 vs 12) showed significant inhibitory effect (IC50 values of 270 microM vs >>1000 microM and 1100 microM vs >>1000 microM on GABA transport, respectively). The cis-trans selectivity can be explained by docking these secoergolines in a three-dimensional model of the second and third transmembrane helices of GABA transporter type 1.
Héja
László
L
Department of Neurochemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1025 Pusztaszeri út 59-67, Organic Chemistry Institute, Budapest University of Technology and Economics, H-1111 Gellért tér 4, Budapest, Hungary.
Kovács
Ilona
I
Szárics
Eva
E
Incze
Mária
M
Temesváriné-Major
Eszter
E
Dörnyei
Gábor
G
Peredy-Kajtár
Mária
M
Gács-Baitz
Eszter
E
Szántay
Csaba
C
Kardos
Julianna
J
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004873:Ergolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018756:GABA Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000596:Amino Acids; D004873:Ergolines; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; C494339:ethyl 4-((ethoxycarbonylmethyl)methylamino)-2-methyl-3-phenylpent-2-enoate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid