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1.
Farmaco ; 56(10): 791-8, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11718273

ABSTRACT

After the identification of GV150526, the indole-2-carboxylate template was further explored in order to identify novel potential anti-stroke agents. In particular, the SAR of the side chain present at the C-3 position of the indole nucleus was widely studied. In this paper, the synthesis and the pharmacological profile of a further class of conformationally restricted analogues of GV150526 as in vitro and in vivo potent glycine antagonists is reported. In particular, a pyrazolidinone derivative was identified as a potent neuroprotective agent in animal models of cerebral ischaemia.


Subject(s)
Glycine/antagonists & inhibitors , Indoles/chemical synthesis , Animals , Binding Sites/drug effects , Indoles/pharmacology , Male , Mice , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/therapeutic use , Rats , Rats, Sprague-Dawley , Seizures/prevention & control , Stroke/prevention & control , Structure-Activity Relationship
2.
Arch Pharm (Weinheim) ; 332(8): 271-8, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10489537

ABSTRACT

A novel series of indole-2-carboxylate analogues of GV150526 (1) in which the propenoic double bond was substituted with different "probes" or replaced by a isosteric cyclopropyl moiety were synthesized and evaluated for their affinity profile in order to obtain further information on the pharmacophoric model of the glycine binding site associated to the NMDA receptor.


Subject(s)
Binding Sites/drug effects , Glycine/antagonists & inhibitors , Indoles/chemistry , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Glycine/metabolism , Indoles/chemical synthesis , Indoles/pharmacology , Mice , Stereoisomerism , Structure-Activity Relationship
3.
Arch Pharm (Weinheim) ; 332(3): 73-80, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10228452

ABSTRACT

A novel series of indole-2-carboxylate analogues of GV 150526 (1) in which the terminal phenyl ring belonging to the side chain present in the position C-3 has been replaced with a bridged cycloalkyl group was synthesized and evaluated for its pharmacological profile. Modelling studies on this class of novel glycine antagonist allowed us to identify an asymmetric lipophilic pocket present in the "North-Eastern" region of the pharmacophoric model of the glycine binding site associated to the NMDA receptor. Among the derivatives prepared, 3-[2-(1-adamantylaminocarbonyl)ethenyl]-4,6-dichloroindole-2 -carboxylic acid 6b and 3-[2-(norbornylaminocarbonyl)ethenyl]-4,6-dichloroindole-2-c arboxylic acid 6l were found to be antagonists acting at the strychnine-insensitive glycine binding site, showing nanomolar affinity for the glycine binding site (Ki = 63 and 19 nM, respectively), coupled with high glutamate receptor selectivity (IC50 > 10(-5) M at the NMDA, AMPA, KA binding sites) and high in vivo potency after systemic administration by inhibition of convulsion induced by NMDA in mice.


Subject(s)
Amantadine/analogs & derivatives , Excitatory Amino Acid Antagonists/chemical synthesis , Indoles/chemical synthesis , Norbornanes/chemical synthesis , Receptors, Glycine/drug effects , Receptors, N-Methyl-D-Aspartate/drug effects , Amantadine/chemical synthesis , Amantadine/pharmacology , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Indoles/pharmacology , Ligands , Mice , Models, Molecular , N-Methylaspartate/pharmacology , Norbornanes/pharmacology , Receptors, Glycine/antagonists & inhibitors , Seizures/chemically induced
4.
Arch Pharm (Weinheim) ; 332(2): 55-8, 1999 Feb.
Article in English | MEDLINE | ID: mdl-10191715

ABSTRACT

A novel series of 3-carbamoylethynyl-2-carboxyindoles, antagonists acting at the strychnine-insensitive glycine binding site associated with the NMDA receptor, has been synthesised. This new versatile approach involves the introduction of a 2-chloroethenyl moiety in position C-3 with subsequent derivatisation of the terminal carboxyl group, followed by an unusual elimination of HCl to afford the ethynyl functionality. This novel series of glycine antagonists was evaluated in terms of in vitro affinity at the glycine binding site and the most potent compound was tested in vivo in the NMDA-induced convulsions model in mice.


Subject(s)
Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Glycine/antagonists & inhibitors , Indoles/chemical synthesis , Indoles/pharmacology , Animals , Binding Sites , Glycine/metabolism , Male , Mice , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism , Structure-Activity Relationship
5.
J Med Chem ; 40(6): 841-50, 1997 Mar 14.
Article in English | MEDLINE | ID: mdl-9083472

ABSTRACT

A series of indole-2-carboxylates bearing suitable chains at the C-3 position of the indole nucleus was synthesized and evaluated in terms of in vitro affinity using [3H]glycine binding assay and in vivo potency by inhibition of convulsions induced by N-methyl-D-aspartate (NMDA) in mice. 3-[2-[(Phenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2-carboxyl ic acid (8) was an antagonist at the strychnine-insensitive glycine binding site (noncompetitive inhibition of the binding of [3H]TCP, pA2 = 8.1) displaying nanomolar affinity for the glycine binding site (pKi = 8.5), coupled with high glutamate receptor selectivity (> 1000-fold relative to the affinity at the NMDA, AMPA, and kainate binding sites). This indole derivative inhibited convulsions induced by NMDA in mice, when administered by both iv and po routes (ED50 = 0.06 and 6 mg/kg, respectively). The effect of the substituents on the terminal phenyl ring of the C-3 side chain was investigated. QSAR analysis suggested that the pKi value decreases with lipophilicity and steric bulk of substituents and increases with the electron donor resonance effect of the groups present in the para position of the terminal phenyl ring. According to these results the terminal phenyl ring of the C-3 side chain should lie in a nonhydrophobic pocket of limited size, refining the proposed pharmacophore model of the glycine binding site associated with the NMDA receptor.


Subject(s)
Excitatory Amino Acid Antagonists/pharmacology , Glycine Agents/pharmacology , Glycine/antagonists & inhibitors , Indoles/pharmacology , Animals , Binding Sites , Binding, Competitive , Carboxylic Acids , Cerebral Cortex/drug effects , Excitatory Amino Acid Antagonists/chemical synthesis , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/metabolism , Glycine/metabolism , Glycine Agents/chemical synthesis , Glycine Agents/chemistry , Glycine Agents/metabolism , Indoles/chemical synthesis , Indoles/chemistry , Indoles/metabolism , Magnetic Resonance Spectroscopy , Mice , Molecular Structure , N-Methylaspartate/pharmacology , Rats , Receptors, Glutamate/metabolism , Structure-Activity Relationship , Strychnine/pharmacology
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