Discovery of α‐Substituted Imidazole‐4‐acetic Acid Analogues as a Novel Class of ρ₁ γ‐Aminobutyric Acid Type A Receptor Antagonists with Effect on Retinal Vascular Tone

Abstract

The ρ-containing γ-aminobutyric acid type A receptors (GABA Rs) play an important role in controlling visual signaling. Therefore, ligands that selectively target these GABA Rs are of interest. In this study, we demonstrate that the partial GABA R agonist imidazole-4-acetic acid (IAA) is able to penetrate the blood-brain barrier in vivo; we prepared a series of α- and N-alkylated, as well as bicyclic analogues of IAA to explore the structure-activity relationship of this scaffold focusing on the acetic acid side chain of IAA. The compounds were prepared via IAA from l-histidine by an efficient minimal-step synthesis, and their pharmacological properties were characterized at native rat GABA Rs in a [ H]muscimol binding assay and at recombinant human α β γ and ρ GABA Rs using the FLIPR™ membrane potential assay. The (+)-α-methyl- and α-cyclopropyl-substituted IAA analogues ((+)-6 a and 6 c, respectively) were identified as fairly potent antagonists of the ρ GABA R that also displayed significant selectivity for this receptor over the α β γ GABA R. Both 6 a and 6 c were shown to inhibit GABA-induced relaxation of retinal arterioles from porcine eyes.

Antagonistic effect of dopamine structural analogues on human GABAρ1 receptor

“…Compared to the other DA metabolites evaluated here, 3-MT turned out to be the most potent modulator of GABAρ1, with a similar potency to DA, suggesting that the methyl moiety in 3-MT does not interfere in ligand binding and may even be important for selectivity of the molecule on ρ1, as described by Krall 38 with imidazolic core antagonists. Therefore, it is possible that the substitution of the catechol core by a benzodioxol could maintain the effect of DA on the ρ1 receptor as well as the selectivity of 3-MT.…”

Rapid and simultaneous determination of histidine metabolism intermediates in human and mouse microbiota and biomatrices

“…L‐histidine is a nutritionally essential amino acid with unique biochemical and physiological properties used to treat rheumatoid arthritis and anemia in patients with chronic renal failure in the past but recently investigated to prevent fatigue during strenuous exercise, as therapy in aging‐related disorders, metabolic syndrome, atopic dermatitis, ulcers, inflammatory bowel diseases, ocular diseases, and neurological disorders and as biomarker of microbially‐induced type II diabetes 7,8,33 . These effects are mediated by histidine and its major bioactive metabolites histamine, N‐acetylhistamine, imidazole‐4‐acetate, cis ‐urocanate, trans ‐urocanate, glutamate, and imidazole propionate 9–34,41 . We developed and validated a simple, rapid and robust method to determine their concentrations in human and mice urine, feces and microbiota metabolome (Figure 4 and Table 6).…”

“…Amino acids are one of the main building blocks of life and are used in a variety of metabolic and physiological forms by the gut microbiota 40 . One of these amino acids, histidine and its bioactive metabolites, have broad physiological effects ranging from neurological development and disorders to dermatologic, metabolic, digestive, vascular and immunosuppressive effects 9–34,41 . Using UHPLC–ESI–MS/MS, we developed a novel method to simultaneously determine histidine and seven bioactive metabolites easily extracted from a small amount of human and mice urine, feces and microbiota metabolome in a single rapid run (6.5 min), enabling a comprehensive assessment of organismal histidine metabolism.…”

“…[11][12][13][14] Histamine is further oxidized to imidazole-4-acetate, a γ-aminobutyric acid-type A receptor agonist, and type C receptor antagonist, whose administration to animals reduces motor activity, enhances seizures, and allodynia and leads to a sleep-like state with seizures. [15][16][17][18] Histamine can alternatively progress to N-acetylhistamine which acts as a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a regulator of body temperature, a vasodilator and a centrally acting neurotransmitter. 19 Excess of dietary histidine is irreversibly degraded to trans-urocanate by the rate-limiting action of histidine ammonia-lyase (HAL) or histidase, an enzyme highly expressed in the surface layer (stratum corneum) of the skin and in the liver.…”

“…Additionally, histamine shows both pro‐inflammatory and anti‐inflammatory effects on immunoregulatory processes and is a major mediator in allergic diseases 11–14 . Histamine is further oxidized to imidazole‐4‐acetate, a γ‐aminobutyric acid‐type A receptor agonist, and type C receptor antagonist, whose administration to animals reduces motor activity, enhances seizures, and allodynia and leads to a sleep‐like state with seizures 15–18 . Histamine can alternatively progress to N‐acetylhistamine which acts as a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a regulator of body temperature, a vasodilator and a centrally acting neurotransmitter 19 .…”