Improved synthesis and in vitro/in vivo activities of natural product-inspired, artificial glutamate analogs

Abstract

Here, we report our second-generation synthesis of 12 artificial glutamate analogs, starting from heterotricycle intermediates 3a-3d, readily prepared in three steps including tandem Ugi/Diels-Alder reactions. The new synthesis employs imidate intermediates for the deoxygenation of pyrrolidones (10a-10d to 6a-6d), and each advanced intermediate 6a--6d was diversified into three glutamate analogs (1a-1d, 5a-5d, 7a-7d) in 1-2 steps.In vitro electrophysiological assays revealed that the new piperidine-type analog 7c alters neuronal function with lower potency than 1a. Conversely, intracranial injection of 7c into mice produced a greater degree of hypoactivity than 1a. Our recent investigation has revealed that this series of compounds antagonizes AMPA-type glutamate receptor-mediated currents in a subtype selective manner. The more efficient syntheses of this novel set of neuroactive molecules will facilitate their pharmacological characterization.

A series of structurally novel heterotricyclic α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate receptor‐selective antagonists

“…Domino metathesis schemes (ring‐opening metathesis/cross metathesis/ring‐closing metathesis) were used to synthesize a family of ‘IKM’ compounds inspired by the naturally occurring convulsant toxins, KA and neoDH (Figure 1) (Ikoma et al ., 2008; Oikawa et al ., 2009; Oikawa et al ., 2010). The IKM molecules are all heterotricyclic hexahydro‐2 H ‐furo[2,3‐c]pyrrole‐dicarboxylic acids with variable third ring components that include substituted pyrans (IKM‐86 and ‐110), oxepanes (IKM‐98 and ‐107) and tetrahydropyridines (IKM‐27 and ‐159).…”

“…In contrast, IKM‐27, IKM‐86 and IKM‐159 induced hypoactive phenotypes similar to cataleptic states (i.e. with marked muscle rigidity), suggesting that their pharmacological activity differed fundamentally from the parent convulsants (Ikoma et al ., 2008; Oikawa et al ., 2009; Oikawa et al ., 2010). Here, we have determined if molecular mechanisms underlying this distinctive behavioural phenotype involved actions on AMPA or KA receptors.…”

Studies on an (S)-2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic Acid (AMPA) Receptor Antagonist IKM-159: Asymmetric Synthesis, Neuroactivity, and Structural Characterization

“…10,13 To purify thoroughly by chromatography, the Ns group in 18 was then replaced with a Boc group by two-step transformation (PhSH, Cs 2 CO 3 , then Boc 2 O) to give N -Boc-amine 19 in 82% yield. 7,10 Finally, all protecting groups were simultaneously removed by hydrolysis with 6 M hydrochloric acid at 65 °C to give rise to (2 R )-IKM-159 ( 2 ) in 92% yield. Chromatographic and spectroscopic data of 2 were completely identical to those of racemic IKM-159.…”

Functionalised Nitrogen Heterocycles and the Search for New Antibacterials and Bioactives

“…Pyroglutamates 2 (R 1 = R 2 = H) are of synthetic interest, 5 particularly for their role in chemical biology 6,7 and drug discovery, 8 and their medicinal significance continues to develop. 7,9 The direct modification of pyroglutamates, using an 8-aminoquinoline amide as a directing group for C-H activation, to access functionalised pyroglutamates has recently been reported.…”

“…Pyroglutamates 2 (R 1 = R 2 = H) are of synthetic interest, 5 particularly for their role in chemical biology 6,7 and drug discovery, 8 and their medicinal significance continues to develop. 7,9 The direct modification of pyroglutamates, using an 8-aminoquinoline amide as a directing group for C-H activation, to access functionalised pyroglutamates has recently been reported. 10 Our initial foray into this area sought to modify a pyroglutamate ester 2 (R 1 = Et) at C-4 by lactam enolate formation followed by alkylation with reactive electrophiles (R 2 = Me, PhCH 2 , CH 2 =CHCH 2 ), but we had difficulty with deprotonations leading to reactions lacking regio-and diastereoselectivity, and also had concerns with the maintenance of enantiocontrol under the conditions of the reaction.…”