The development of 2,3,7,8-tetrachlorophenothiazine as a drug lead

Abstract

The dioxin analogue 2,3,7,8-tetrachlorophenothiazine (TCPT) was synthesized and developed as a drug lead with potential applications in chemoprevention, body weight control, type II diabetes, contraception, and longevity. These well-documented effects of dioxins are believed to be mediated through two key mechanisms of action: AhR binding with downsteam induction of enzyme activity, and reduced IGF-1 signaling. The effects of TCPT on these pathways were investigated quantitatively.

TCPT showed an affinity to AhR similar to that of TCDD, and it induced EROD activity with high efficacy in vitro. Its potency regarding enzyme induction, however, was lower by two orders of magnitude compared to that of TCDD. Metabolism was demonstrated to yield low-potency derivatives.

Dose-response relationships were developed for TCPT and TCDD regarding the reduction of serum IGF-1 levels in the rat. TCPT displayed in this regard also high efficacy, but very low potency compared to TCDD.

Unlike TCDD, TCPT did not affect thyroid homeostasis at doses that lowered IGF-1 signaling. These findings suggest that TCPT could become a suitable drug lead.