Synthesis and Structure-Activity Studies on Excitatory Amino Acids Structurally Related to Ibotenic Acid

Abstract

With use of ibotenic acid as a lead, analogues of (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and of (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA) were synthesized and tested as excitants of neurons in the cat spinal cord by using microelectrophoretic techniques and as inhibitors of the binding of kainic acid in vitro. Like AMPA and 7-HPCA, (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridine-5-carboxylic acid (10, 5-HPCA) and (RS)-3-hydroxy-5-(bromomethyl)isoxazole-4-propionic acid (11, ABPA) proved to interact potently and selectively with central quisqualic acid receptors, assumed to represent physiological glutamic acid receptors. Analogues of 7-HPCA or 10, in which one or both of the acid groups were masked, were very weak or inactive as neuronal excitants and had no antagonistic effects at excitatory amino acid receptors. The structure of 7-HPCA in the crystalline state was established by X-ray analyses. The preferred conformation of 10 in aqueous solution was determined by 1H NMR spectroscopy. On the basis of these studies, 7-HPCA as well as 10 were shown to adopt preferentially conformations with the carboxylate groups in equatorial positions. It is suggested that AMPA, 7-HPCA, and 10 interact with quisqualic acid receptors in conformations essentially reflecting active conformation(s) of glutamic acid at these receptors.

O-Methyl-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol Hydrochloride, O-Me-THPO.HCl

“…Crystal data (3) 112.8(2) 1.425 (3) 112.6(2) 1.420 (3) 112.9(2) References: AMIOXO, Brehm (1977); HAPIOX, Brehm & KrogsgaardLarsen (1974); HMUSCM, ISAZOL, Brehm & Larsen (1976); DECJAW/DECJAW01, Krogsgaard-Larsen et al (1985); DEVFEP, Brehm et al (1985); GASKUG, Madsen et al (1988); RSAMPA, Honor6 & Lauridsen (1980); SEBFUA, Hansen et al (1989); OPOXAZ/OPOXAZ01, Biagini et al (1969a,b); (R)-APPA, Ebert et al (1994).…”

Structural, conformational, and stereochemical requirements of central excitatory amino acid receptors

“…In this bicyclic analogue the structural element of AMPA is locked in a fixed conformation, and 5-HPCA was found to be a selective QUIS1AMPA receptor agonist, only slightly weaker than AMPA, with no effect on NMDA receptors in vivo or KAIN receptors in vitro (236). The solid-state conformation of AMPA (Fig.…”

“…Several analogues of AMPA (see Fig. 12), including D~-a-amino-3-hydroxy-5-bromomethyl-4-isoxazolepropanoic acid (ABPA) and DL-a-amino-3-hydroxy-5-tert.-butyl-4-isoxazolepropanoic acid (ATBA), are, like AMPA, selective QUISiAMPA receptor agonists with little effect on NMDA receptors in vivo or KAIN receptors in vitro (236,237). ABPA contains the chemically reactive bromomethyl group and was designed as an analogue capable of irreversibly alkylating the receptor.…”

“…In order to elucidate the active conformation of AMPA, the conformationally restricted analogue ~~-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA) was synthesized and biologically tested (236). In this bicyclic analogue the structural element of AMPA is locked in a fixed conformation, and 5-HPCA was found to be a selective QUIS1AMPA receptor agonist, only slightly weaker than AMPA, with no effect on NMDA receptors in vivo or KAIN receptors in vitro (236).…”

“…X-ray crystallographic analysis (Fig. 14) has shown, that 7-HPCA in the solid state contains the sixmembered ring in a half-chair conformation with the carboxyl group in a pseudoequatorial position (236). This conformation of 7-HPCA is very similar to the conformation observed for 5-HPCA, and, in fact, the fully ionized molecules of 5-HPCA and 7-HPCA can achieve very similar shapes and charge distributions due to delocalization of the negative charge on the 3-isoxazolol moieties (201).…”