Dienogest Derivatives Show Increased Selectivity to the Progesterone Receptor

Abstract

Progestin, the synthetic progesterone in the combination birth control pill, functions to prevent pregnancy. Unfortunately, it also results in a wide range of side effects associated with the pill, including nausea, headaches, abdominal cramping, breakthrough bleeding, and mood changes. These side effects are due to the interactions that take place when the progestin binds not only to its desired target, the progesterone receptor, but also to other steroid receptors, namely the androgen receptor, estrogen receptor, glucocorticoid receptor, and mineralocorticoid receptor. In hopes of diminishing these side effects, in this study, one progestin, dienogest, was computationally altered to improve binding to the progesterone receptor while minimizing the binding to other receptors. The most successful derivative created involved the addition of a methyl and a methylene group, which significantly decreased binding to the five other receptors while maintaining a similar affinity for the progesterone receptor. Importantly, in an assessment of the social aspect of the birth control pill via an online survey released in the San Francisco Bay Area (n=73), the side effects of the birth control pill, which could be improved by minimizing off target interactions, are a major concern among women who consider this form of contraception.