Novel Secoergoline Derivatives Inhibit Both GABA and Glutamate Uptake in Rat Brain Homogenates:  Synthesis, in Vitro Pharmacology, and Modeling

• Published in: Journal of medicinal chemistry Vol. 47; no. 23; pp. 5620 - 5629
• Main Authors: Héja, László, Kovács, Ilona, Szárics, Éva, Incze, Mária, Temesváriné-Major, Eszter, Dörnyei, Gábor, Peredy-Kajtár, Mária, Gács-Baitz, Eszter, Szántay, Csaba, Kardos, Julianna
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 04.11.2004; Amer Chemical Soc
• Subjects: Amino Acids - chemical synthesis; Amino Acids - chemistry; Amino Acids - pharmacology; Animals; Biological and medical sciences; Biological Transport - drug effects; Brain - drug effects; Brain - metabolism; Chemistry, Medicinal; Ergolines - chemical synthesis; Ergolines - chemistry; Ergolines - pharmacology; Excitatory Amino Acid Antagonists - chemical synthesis; Excitatory Amino Acid Antagonists - chemistry; Excitatory Amino Acid Antagonists - pharmacology; GABA Antagonists - chemical synthesis; GABA Antagonists - chemistry; GABA Antagonists - pharmacology; gamma-Aminobutyric Acid - metabolism; Glutamatergic system (aspartate and other excitatory aminoacids); Glutamic Acid - metabolism; In Vitro Techniques; Life Sciences & Biomedicine; Male; Medical sciences; Models, Molecular; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Radioligand Assay; Rats; Rats, Wistar; Science & Technology; Stereoisomerism; Structure-Activity Relationship; AFFINITY; MEMBRANES; SITES; GAT-1; MECHANISMS; AMINO-ACID TRANSPORTERS; EPILEPSY; IDENTIFICATION; PROTEINS; BINDING; Rat; Central nervous system; Modeling; Encephalon; Pyridine derivatives; Aminoester; Structure activity relation; Membrane transport; Vinylic compound; Molecular model; Inhibition; Chemical synthesis; Carrier protein; Aliphatic compound; Rodentia; Benzene derivatives; Glutamate; In vitro; Uptake; α-Aminoacid; Vertebrata; Three dimensional model; Mammalia; Animal; GABA
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm040809c

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 μM, 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 μM 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 μM vs ≫1000 μM and 1100 μM vs ≫1000 μM 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.