Identification and optimization of small molecule antagonists of vasoactive intestinal peptide receptor-1 (VIPR1)

Mechanisms involved in VPAC receptors activation and regulation: lessons from pharmacological and mutagenesis studies

“…A key limiting factor in this field is that all the currently useful pharmacological tools are peptides, and thus limit their use in human therapy. The first small molecule antagonists of VPAC 1 (Harikrishnan et al, 2012) and VPAC 2 (Chu et al, 2010) have been described recently and emerge from high throughput screening of compound collection. However, all are low affinity, micro molar range, antagonists and need further improvement to expect to obtain druggable modulators of VPAC receptors activity.…”

Palladium-Catalyzed Regioselective 2-Carbethoxyethylation of 1H– Indoles By C-H Activation: One-Step Synthesis of Ethyl 2-(1H-Indol-2-Yl) Acetates

“…Given the possibility that excessive water in the solvent might hydrolyse the arylpalladium(II) species formed in the first oxidative addition step and lower the solubility of the intermediates, resulting in a cessation of the catalytic cycle and undesired conversion rate, we switched the solvent back to DMF with 0.5M H 2 O. Finally, a brief screen of bases showed an interesting correlation between the alkalinity of the base and the yield of the 2,3-disubstitued-indole byproduct 2 ( Table 1, [11][12][13][14][15]. Specifically, the yields of the 2,3-disubstitued-indole products increased significantly as the alkalinity of the base increased, with NaHCO 3 affording the target products in desirable yields.…”

“…Among them, 2-(1H-indol-2-yl)acetic acids constitute a valuable class of building blocks for natural product and natural product analogue syntheses ( Figure 1) [4][5][6][7], combinatorial [8], diversity-oriented syntheses [9,10], and medicinal chemistry [11][12][13][14][15][16][17][18]. In addition, they can serve as highly attractive precursors for various chemical transformations, such as diazomethylation to 1-diazo-3-(2-indolyl)-2-propanone [19] and reduction to 2-(2-hydroxyethyl) indole [20].…”

Potential PET Ligands for Imaging of Cerebral VPAC and PAC Receptors: Are Non-Peptide Small Molecules Superior to Peptide Compounds?

“…VPAC1 is expressed in lung, small intestine, thymus, kidney and brain [10] [63] [78] [89] [90]. In the brain VPAC receptors are expressed in piriform cortex, cerebral cortex, dentate gyrus, hippocampus, lateral amygdaloid nucleus, caudate putamen, nucleus supraopticus, thalamic nuclei, choroid plexus and pineal gland as well as cerebellar cortex and deep cerebellar nuclei [11] [77].…”