Cyclic Enecarbamates as Precursors of α,β-Unsaturated Iminium Ions: Reactivity and Synthesis of 6,6-Spirocyclic Ring Systems

The scalable synthesis of cyclic enecarbamates and their use as convenient precursors of α,β-unsaturated <i>N</i>-acyl iminium ions is reported. The newly developed route overcomes synthetic and reactivity difficulties in previously reported methods, is readily scaled up, and proceeds through stable intermediates suitable for long-term storage if required. Preliminary investigations probing the reactivity of cyclic α,β-unsaturated <i>N</i>-acyl iminium ions as dienophiles in Diels–Alder reactions and electrophilic alkylating agents are described. In the presence of Lewis and Brønsted acids, iminium precursor <b>22a</b> underwent efficient Diels–Alder cycloaddition with a range of simple and complex dienes, culminating in the synthesis of 6,6-spirocyclic ring systems possessing the same relative stereochemistry as the spirocyclic imine present in the marine natural product gymnodimine <b>1</b>

Novel Aza-analogous Ergoline Derived Scaffolds as Potent Serotonin 5‑HT₆ and Dopamine D₂ Receptor Ligands.

By introducing distal substituents on a tetracyclic scaffold resembling the ergoline structure, two series of analogues were achieved exhibiting subnanomolar receptor binding affinities for the dopamine D₂ and serotonin 5-HT₆ receptor subtype, respectively. While the 5-HT₆ ligands were antagonists, the D₂ ligands displayed intrinsic activities ranging from full agonism to partial agonism with low intrinsic activity. These structures could potentially be interesting for treatment of neurological diseases such as schizophrenia, Parkinson’s disease, and cognitive deficits

Structure–Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2<i>S</i>,3<i>R</i>)‑3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid

Herein we describe the first structure–activity relationship study of the broad-range iGluR antagonist (2<i>S</i>,3<i>R</i>)-3-(3-carboxyphenyl)­pyrrolidine-2-carboxylic acid (<b>1</b>) by exploring the pharmacological effect of substituents in the 4, 4′, or 5′ positions and the bioisosteric substitution of the distal carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4′ position <b>2a</b> which induced a preference in binding affinity for homomeric GluK3 over GluK1 (<i>K</i>_i = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: <b>2e</b> in GluA2-LBD and <b>2f</b> in GluK1-LBD, both at 1.9 Å resolution. Compound <b>2e</b> induces a D1–D2 domain opening in GluA2-LBD of 17.3–18.8° and <b>2f</b> a domain opening in GluK1-LBD of 17.0–17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of <b>2e</b> and <b>2f</b> shows a similar binding mode as kainate. The 3-carboxyphenyl ring of <b>2e</b> and <b>2f</b> forms contacts comparable to those of the distal carboxylate in kainate

Design and Synthesis of a Series of l-<i>trans</i>-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X‑ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2<i>S</i>,4<i>R</i>)‑4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid

Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2<i>S</i>,4<i>R</i>)-4-(2-carboxyphenoxy)­pyrrolidine-2-carboxylic acid (<b>1b</b>), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (<i>K</i>_i = 4 μM). In a functional assay, <b>1b</b> displayed full antagonist activity with IC₅₀ = 6 ± 2 μM. A crystal structure was obtained of <b>1b</b> when bound in the ligand binding domain of GluK1. A domain opening of 13–14° was seen compared to the structure with glutamate, consistent with <b>1b</b> being an antagonist. A structure–activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor