A Diversity Oriented Synthesis Approach to New 2,3-trans-Substituted l-Proline Analogs as Potential Ligands for the Ionotropic Glutamate Receptors

Abstract

Discovery of chemical tools for the ionotropic glutamate receptors continues to be a challenging task. Herein we report a diversity-oriented approach to new 2,3-trans-l-proline analogs whereby we study how the spatial orientation of the distal carboxylate group influences the binding affinity and receptor class and subtype selectivity. In total, 10 new analogs were synthesized and 14 stereoisomers characterized in binding assays at native rat ionotropic glutamate receptors, and at cloned human homomeric kainic acid (KA) receptor subtypes GluK1–3. The study identified isoxazole analogs 3d,e, which displayed selectivity in binding at native N-methyl-d-aspartate (NMDA) receptors over native α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and KA receptors, in the high nanomolar to low micromolar range. Furthermore, analogs 3i-A/B showed a preference in binding affinity for GluK3 over GluK1,2. Finally, analog 3j displayed high nanomolar affinity for native NMDA receptors as well as for homomeric GluK3 receptors.

Palladium-catalysed Csp3–H functionalisation of unactivated 8-aminoquinoline amides in deep eutectic solvents

“…Since then, several groups have used this strategy of alkynylation based on the 8-aminoquinoline directing group, but in all the cases, stoichiometric amounts of silver salts were required. [31][32][33][34][35][36] With this approach using DESs, the optimised conditions for the arylation were directly applied to the alkynylation of 2aa, obtaining a good isolated yield in betaine : HFIP (1 : 2) and avoiding the use of silver derivatives (Scheme 2).…”

Synthesis and Reactivity of 3‐Halo‐4,5‐dihydroisoxazoles: An Overview

“…The generation of the other by‐products dibromo 1,2,4‐oxadiazole‐4‐oxide and dibromo 1,4,2,5‐dioxadiazine is indeed kinetically disfavored [48] . Notably, the side self‐reaction rate can be dramatically reduced, leading to a marked improvement of the yields, by slowing down the activation of DBF using a poorly soluble inorganic base (e. g., sodium bicarbonate) in organic solvents as dichloromethane, [49,50] THF [51] or ethyl acetate [52] . However, this reaction can be carried out also in more polar solvents such as water [40] and DMF [53,54] or using organic bases such as DBU [55] or TEA [56] .…”

“…During the reaction, which occurs with a concerted mechanism, the two participants are oriented on two parallel planes in which the three orbitals of the dipole and the two of the dipolarophile are combined in a suprafacial/suprafacial way, leading to the formation of a five‐membered isoxazoline ring with syn substituents from alkene cis groups and anti substituents from trans . Although in the case of achiral olefins the attack can occur from both faces giving a mixture of stereoisomers, a partial [33,52,72] or total [55,67,73] stereoselectivity can be achieved for alkenes bearing one or more asymmetric centers, especially if located close to the reactive double bond. The preferential suprafacial attack can be influenced by steric factors (attack on the less hindered face) or by the unsaturation of weak dipole‐dipolarophile interactions.…”

“…In particular, the 3‐isoxazolidinone scaffold is present in the natural amino acid Tricholomic acid ( 24) and in various derivatives active on the glutamate neurotransmission system ( 25 and 26 , Scheme 10). [52,68,95–99] …”

(S)-2-Mercaptohistidine: A First Selective Orthosteric GluK3 Antagonist

“…The success rate of developing competitive agonists and antagonists that differentiate between the AMPA, KA, and NMDA receptors is relatively high. − Despite extensive efforts, however, the success rate for the development of subtype-selective orthosteric ligands within each of these iGluR families has been very low, especially true for the KA receptor. In fact, only GluK1 subtype-selective agonists and antagonists and the two GluK3-selective agonists CIP-AS ( 1a ) (GluK1/GluK3 = 110-fold; GluK2/GluK3 = 27-fold) , and LBG-20130 ( 1b ) (GluK1/GluK3 = ∼15-fold; GluK2/GluK3 = >15-fold) have been disclosed to this date …”