Structure−Activity Relationships in a Series of 2(1H)-Quinolones Bearing Different Acidic Function in the 3-Position:  6,7-Dichloro-2(1H)-oxoquinoline-3-phosphonic Acid, a New Potent and Selective AMPA/Kainate Antagonist with Neuroprotective Properties

Abstract

Recently, we reported the synthesis of 3-(sulfonylamino)-2(1H)-quinolones, a new series of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate and N-methyl-D-aspartic acid (NMDA)/glycine antagonists. By exploring the structure-activity relationships (SAR) in this series, we were able to identify the 6,7-dinitro derivative 6 as a potent and balanced antagonist at both receptors. Unfortunately, compound 6 was devoid of in vivo activity in mice anticonvulsant testing. To overcome this critical limitation, new compounds bearing various acidic moieties at the 3-position of the quinolone skeleton were synthesized and evaluated. The SAR of these new analogues indicated that not all acidic groups are acceptable at the 3-position: A rank order of potency going from carboxylic approximately phosphonic > tetrazole > mercaptoacetic > hydroxamic >> other heterocyclic acids was defined. In addition, the selectivity between the AMPA/kainate and NMDA/glycine sites is dependent on the nature of the substitution (nitro > chloro for AMPA selectivity), its position (5,7- > 6,7-pattern for glycine selectivity), and the distance between the quinolone moiety and the heteroatom bearing the acidic hydrogen (the longer the distance the more AMPA selective the compound). Among these new AMPA antagonists, we have identified 6,7-dichloro-2(1H)-oxoquinoline-3-phosphonic acid (24c) as a water soluble and selective compound endowed with an appealing pharmacological profile. Compared with the reference AMPA antagonist NBQX, the phosphonic acid 24c is much less potent in vitro but almost equipotent in vivo in the audiogenic seizures model after intraperitoneal administration. Moreover, unlike NBQX, compound 24c is also active after oral administration. In the gerbil global ischemia model, compound 24c shows a neuroprotective effect at 10 mg/kg/ip, equivalent to the reference NBQX.

Glutamate Receptor Ion Channels: Activators and Inhibitors

“…A range of quinoxalinediones displayed similar or improved anticonvulsant activity compared to NBQX (OHMORI et al 1994(OHMORI et al , 1997WATJEN et al 1994;BIGGE et al 1995;DESOS et al 1996;LUBISCH et al 1996). No impairment of motor function was observed at anticonvulsant doses of NS257 (Fig.…”

“…3) (WATJEN et al 1994). A number of quinoxalinedione analogues had improved neuroprotective properties over NBQX (OHMORI et al 1994;WATJEN et al 1994;BIGGE et al 1995;DESOS et al 1996;TAKAHASHI et al 1998). These improvements in the in vivo activity are likely to be due to the higher water solubility of some of the quinoxalinedione analogues tested (WATJEN et al 1994;DESOS et al 1996;TAKAHASHI et al 1998).…”

“…hICso value taken from WATJEN et al (1994). i NBQX is reference substance for S 17625; ICso values taken from DESOS et al (1996). i Taken from LUBISCH et al (1996).…”

“…A series of 2(lH)-quinolones bearing different acidic groups at the 3-position have been reported to be potent and selective AMPA receptor antagonists (DESOS et al 1996). A structure-activity study revealed that a 3-phosphono substituent conferred optimal potency and selectivity for AMPA receptors.…”

“…The 6,7-dichloro analogue (6,7-dichloro-2(lH)-oxoquinoline-3-phosphonic acid, S 17625, Fig. 3) had lower affinity than NBQX for displacement of [3H]AMPA (Table 1) but was equipotent in vivo as an anticonvulsant (DESOS et al 1996).…”