Synthesis and Characterization of Iodinated Tetrahydroquinolines Targeting the G Protein-Coupled Estrogen Receptor GPR30

Abstract

A series of iodo-substituted tetrahydro-3H-cyclopenta[c]quinolines was synthesized as potential targeted imaging agents for the G protein-coupled estrogen receptor GPR30. The affinity and specificity of binding to GPR30 versus the classical estrogen receptors ERα/β and functional responses associated with ligand-binding were determined. Selected iodo-substituted tetrahydro-3H-cyclopenta[c]quinolines exhibited IC 50 values lower than 20 nM in competitive binding studies with GPR30-expressing human endometrial cancer cells. These compounds functioned as antagonists of GPR30 and blocked estrogen-induced PI3K activation and calcium mobilization. The tributylstannyl precursors of selected compounds were radiolabeled with 125 I using the iodogen method. In vivo biodistribution studies in female ovariectomized athymic (NCr) nu/nu mice bearing GPR30-expressing human endometrial tumors revealed GPR30-mediated uptake of the radiotracer ligands in tumor, adrenal and reproductive organs. Biodistribution and quantitative SPECT/CT studies revealed structurally-related differences in the pharmacokinetic profiles, target tissue uptake and metabolism of the radiolabeled compounds as well as differences in susceptibility to deiodination. The high lipophilicity of the compounds adversely affects the in vivo biodistribution and clearance of these radioligands, and suggests that further optimization of this parameter may lead to improved targeting characteristics.

Chemistry: Chemical con artists foil drug discovery

“…Sometimes a molecule fails only after going through patenting and assessment in animals 6 . It is regrettably easy, in our experience, to get a misleading readout in an animal model that is not related to the anticipated mechanism of action.…”

Macromolecular Modelling and Docking Simulations for the Discovery of Selective GPER Ligands

“…A first success was the identification of the selective agonist chemical G-1 (24), which was obtained by a virtual and biomolecular screening approach. This compound paved the way for the development of further molecules based on the same scaffold, however, exhibiting antagonistic activity as G-15 and G-36 (25,26,28). In parallel, two novel molecules with completely different scaffolds were designed and identified as GPER ligands by docking simulations (29).…”

“…Using the aforementioned approaches, several different natural and synthetic ligands of GPER (Fig. 1) have been identified along with their binding modes as resulting from docking simulations (13,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

Bleaching earth clay (pH 12.5)/PEG-400: an efficient recyclable catalytic system for synthesis of 5,6,7,8-tetrahydroquinoline-3-carbonitrile derivatives

“…The tetrahydroquinoline framework is considered to be one of the privileged structures in the area of drug discovery, as compounds containing this scaffold display a wide range of biological and pharmaceutical activities [4][5][6][7][8][9][10][11][12], including anti-human immunodeficiency virus (HIV) [13,14], anticancer [15,16], and antimalarial action [17], cholesteryl ester transfer protein inhibition [18], antidiabetic [19] and antifungal activity [20], C 5a receptor antagonism [21], RET tyrosine kinase inhibition [22], etc.…”