Ergoline‐Derived Inverse Agonists of the Human H3 Receptor for the Treatment of Narcolepsy

Abstract

Ergoline derivative (6aR,9R)-4-(2-(dimethylamino)ethyl)-N-phenyl-9-(pyrrolidine-1-carbonyl)-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-7(4H)-carboxamide (1), a CXCR3 antagonist, also inhibits human histamine H3 receptors (H3R) and represents a structurally novel H3R inverse agonist chemotype. It displays favorable pharmacokinetic and in vitro safety profiles, and served as a lead compound in a program to explore ergoline derivatives as potential drug candidates for the treatment of narcolepsy. A key objective of this work was to enhance the safety and efficacy profiles of 1, while minimizing its duration of action to mitigate the episodes of insomnia documented with previously reported clinical candidates during the night following administration. Modifications to the ergoline core at positions 1, 6 and 8 were systematically investigated, and derivative 23 (1-((4aR,8R,9aR)-8-(hydroxymethyl)-1-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)-4,4a,7,8,9,9a-hexahydroindolo[1,14-fg]quinolin-6(1H)-yl)ethanone) was identified as a promising lead compound. Derivative 23 has a desirable pharmacokinetic profile and demonstrated efficacy by enhancing brain concentrations of tele-methylhistamine, a major histamine metabolite. This validates the potential of the ergoline scaffold to serve as a template for the development of H3R inverse agonists.

Orexin deficiency modulates cognitive flexibility in a sex‐dependent manner

“…Orexin levels are not only altered in narcolepsy but also in inattentive subtype of attention‐deficit/hyperactivity disorder (ADHD) 66 . Homozygous orexin‐deficient mice exhibited sleep disturbances similar to human narcolepsy and are used as narcoleptic mice models 23,67 . Narcoleptic episodes are triggered by emotional stimuli in human narcoleptic patients as well as in homozygous orexin‐deficient mice 68,69 .…”

Agonist‐induced activation of histamine H3 receptor signals to extracellular signal‐regulated kinases 1 and 2 through PKC‐, PLD‐, and EGFR‐dependent mechanisms

“…; Auberson et al . ). Evidence gathered over the years has also demonstrated the prominent role of neuronal H3R in the prevention of neuronal damage (Lintunen et al .…”

“…; Auberson et al . ). There is also evidence to show that the H3 receptor is implicated in neuroprotection in the CNS (Adachi et al .…”

From Ergolines to Indoles: Improved Inhibitors of the Human H3 Receptor for the Treatment of Narcolepsy

“…[2] All drug candidates developed so far have a prolonged pharmacological effect, and as a consequence perturb sleep during the night following administration. [3] Therapeutic agents capable of inducing a shortterm increase in wakefulness have been elusive so far, even though ergolines were recently identified as a novel class of H3R inverse agonists with a short duration of action. [3] While their optimization led to drug candidates with encouraging properties, a high level of P-glycoprotein (Pgp)-mediated efflux could not be rectified.…”

“…[3] Therapeutic agents capable of inducing a shortterm increase in wakefulness have been elusive so far, even though ergolines were recently identified as a novel class of H3R inverse agonists with a short duration of action. [3] While their optimization led to drug candidates with encouraging properties, a high level of P-glycoprotein (Pgp)-mediated efflux could not be rectified. This led to low brain penetration and receptor occupancy levels unlikely to provide a strong wake-promoting effect in human narcolepsy patients.…”