2-Phenylimidazo[1,2-a]pyridine-containing ligands of the 18-kDa translocator protein (TSPO) behave as agonists and antagonists of steroidogenesis in a mouse leydig tumor cell line

Eur J Pharm Sci. 2015 Aug 30:76:231-7. doi: 10.1016/j.ejps.2015.05.021. Epub 2015 May 19.

Abstract

Ligands of 18-kDa translocator protein (TSPO) are known for their ability to potently and dose-dependently stimulate steroid biosynthesis in steroidogenic cells. In this study, we investigated a number of 2-phenyl-imidazo[1,2-a]pyridine acetamide derivatives, analogs of alpidem, for their ability to bind TSPO and to affect steroidogenesis in a mouse Leydig tumor cell line. We observed that not only some compounds behaved as agonists, stimulating steroidogenesis (e.g., 3 and 4) with EC50 values (15.9 and 6.99μM) close to that determined for FGIN-1-27 used as positive control (7.24μM), but two compounds, namely 5 and 6, which on the other hand are the most lipophilic ones in the investigated series, behaved as antagonists, by significantly inhibiting steroid production at concentrations at least twenty times lower than the cytotoxic ones. To our surprise, the newly synthesized compound 3, which is a strict analog of alpidem bearing at the para position of the 2-phenyl group a methoxy group instead of chlorine, achieved a ten-fold stimulation of the steroid production (for comparison FGIN-1-27 achieved 1.6-fold stimulation). Within the limits of the examined property space, some unprecedented SARs were unveiled, which can help in understanding the key molecular factors underlying the transition from agonism to antagonism in the steroidogenesis process. Besides the substitution pattern and the physicochemical features (mainly hydrogen bonding potential) of the substituents at the positions C(6) and C(8) of the imidazo[1,2-a]pyridine nucleus, and at the para position of the 2-phenyl group, the structure-activity relationship analysis suggested lipophilicity, whose increase seems to be generally related to steroidogenesis inhibition, and steric hindrance, which appeared as a stimulation-limiting factor, as two main properties to control in the design or optimization of novel imidazo[1,2-a]pyridine-based TSPO ligands endowed with potential in modulating the steroidogenesis process.

Keywords: 18-kDa translocator protein; Imidazo[1,2-a]pyridine; Leydig tumor cell line; Steroidogenesis; TSPO.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Hormonal / chemical synthesis
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Hormone Antagonists / chemical synthesis
  • Hormone Antagonists / pharmacology*
  • Hydrogen Bonding
  • Imidazoles / chemical synthesis
  • Imidazoles / pharmacology*
  • Leydig Cell Tumor / drug therapy*
  • Leydig Cell Tumor / metabolism
  • Leydig Cell Tumor / pathology
  • Ligands
  • Male
  • Mice
  • Molecular Structure
  • Neoplasms, Hormone-Dependent / drug therapy*
  • Neoplasms, Hormone-Dependent / metabolism
  • Neoplasms, Hormone-Dependent / pathology
  • Pyridines / chemical synthesis
  • Pyridines / pharmacology*
  • Receptors, GABA / drug effects*
  • Receptors, GABA / metabolism
  • Steroid Synthesis Inhibitors / chemical synthesis
  • Steroid Synthesis Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Testicular Neoplasms / drug therapy*
  • Testicular Neoplasms / metabolism
  • Testicular Neoplasms / pathology

Substances

  • Antineoplastic Agents, Hormonal
  • Bzrp protein, mouse
  • Hormone Antagonists
  • Imidazoles
  • Ligands
  • Pyridines
  • Receptors, GABA
  • Steroid Synthesis Inhibitors
  • alpidem