Tweaking Subtype Selectivity and Agonist Efficacy at (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) Receptors in a Small Series of BnTetAMPA Analogues

Abstract

A series of analogues of the (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptor agonist BnTetAMPA (5b) were synthesized and characterized pharmacologically in radioligand binding assays at native and cloned AMPA receptors and functionally by two-electrode voltage clamp electrophysiology at the four homomeric AMPA receptors expressed in Xenopus laevis oocytes. The analogues 6 and 7 exhibit very different pharmacological profiles with binding affinity preference for the subtypes GluA1 and GluA3, respectively. X-ray crystal structures of three ligands (6, 7, and 8) in complex with the agonist binding domain (ABD) of GluA2 show that they induce full domain closure despite their low agonist efficacies. Trp767 in GluA2 ABD could be an important determinant for partial agonism of this compound series at AMPA receptors, since agonist efficacy also correlated with the location of the Trp767 side chain.

Use of the 4-Hydroxytriazole Moiety as a Bioisosteric Tool in the Development of Ionotropic Glutamate Receptor Ligands

“…Interestingly, 6b binds in a mode similar to AMPA (Figure 5C), whereas other AMPA-related agonists containing a larger substituent than a methyl group in the 5-position (corresponding to the N(c)-position in 6b), such as t-butyl group (ATPA), 46 2-methyl-tetrazole (MeTetAMPA), 47 or benzyltetrazole (BnTetAMPA), 22 have been shown to switch to a binding mode similar to Glu. 44 Therefore, compound 6a (N(c)-methyl) would most likely also bind in the AMPA binding mode, whereas 6c (N(c)-propyl) probably would switch to the glutamate binding mode due to otherwise steric clash with the residues forming the hydrophobic pocket.…”

“…The combined organic layers were collected, dried, and concentrated in vacuo. The (22). Pd/C (10% w/w, 24 mg) and a saturated solution of hydrochloric acid in dry EtOH were added to a solution of 21 (0.789 mmol, 240 mg) in dry EtOH (35 mL) kept under an inert atmosphere.…”

“…Nevertheless, some compounds (Figure ) such as ( RS )-2-amino-3-(4-chloro-3-hydroxyisoxazol-5-yl)­propionic acid (Cl-HIBO, 3 ) and ( RS )-3-hydroxy-4,5,6,7-tetrahydroisoxazolo­[5,4- c ]­pyridine-7-carboxylic acid (7-HPCA, 4 ) are able to selectively activate GluA1/2, , exploiting the only difference between GluA1/2 and Glu3/4 among the amino acids in direct contact with Glu. Some preference toward GluA1 and GluA3 has been achieved by the continued development of 2-methyl-tetrazole-AMPA (MeTetAMPA) ( 5a ) through benzyl-tetrazole-AMPA (BnTetAMPA) ( 5b ) to aminomethyl- and chloro-substituted BnTetAMPA analogues 5c and 5d , respectively. − The protrusion of the benzyl group in BnTetAMPA into a less conserved area is enabled by the movement of a conserved methionine (Met729 in GluA2) in the binding pocket, leading to the observed variation in the selectivity profiles of these analogues.…”

Synthesis and development of seven-membered constrained cyclic urea based PSMA inhibitors via RCM

“…Initial attention focused on the synthesis of allyl glutamate 4 , beginning with conversion of glutamate 6 to 2-nitrophenylsulfonyl (2-nosyl) N α -protected 8 in 72% yield using a selective mono 2-nitrobenzene-1-sulfonyl chloride protocol described by Wang et al (Scheme 3). 35 This strategy was implemented to promote selective mono allyl alkylation in the ensuing steps, in addition to enabling a higher yielding alkylation on the secondary amine 8 through 2-nosyl acting as an activating group. We avoided using the para 4-nitrobenzene-1-sulfonyl chloride due to the reported difficulty in effective removal of this structural isomer.…”

“…30,[32][33][34] Initial attention focused on the synthesis of allyl glutamate 4, beginning with conversion of glutamate 6 to 2-nitrophenylsulfonyl (2-nosyl) N a -protected 8 in 72% yield using a selective mono 2-nitrobenzene-1-sulfonyl chloride protocol described by Wang et al (Scheme 3). 35 This strategy was implemented to Scheme 1 Formation of cyclized side products via condensation/ dehydration reported by Martin et al 21 Scheme 2 Retrosynthetic rationale to the design of cyclic PSMA inhibitor (1b).…”