ADX-10061

This paper details the first study of the effects of dopamine D1 receptor antagonism on the regulation of human sleep EEG (electroencephalogram). The investigational drug NNC-687 (NNC 01-0687/CEE 03-310) was administered to 20 healthy young men in doses of 5, 10, and 15 mg in a double blinded, placebo controlled, crossover design. In rats, dopamine D1 receptor antagonism can produce large increases in the amounts of both rapid eye-movement (REM) and non-rapid eye-movement (NREM) sleep. In this study, drug effects were most prominent in the first NREM period. D1 antagonism markedly reduced the peak-amplitude of delta EEG waves but increased their instantaneous frequency as well as enhancing the total number, incidence, and burst-duration of sleep spindles. The length of the first NREM period was increased up to 47% over baseline. Despite these large increases in NREM sleep time, the amount of delta EEG power accumulated over the first NREM period was conserved at baseline levels. We note that the sleep-EEG profile of D1 antagonism is very similar to that of GABAA (gamma-aminobutyric acid) receptor modulators and suggest that D1 antagonism may alter the properties of the neuronal networks which generate delta and spindle, and K-complex EEG waveforms through the upstream modulation of GABAA receptor activity.

CEE-03-310 is a selective dopamine D1-like receptor antagonist with no appreciable binding affinity for other receptors. Although originally developed by Novo Nordisk A/S as NNC-687 for the treatment of schizophrenia, the company changed its therapeutic focus in the mid-1990s and the full rights to CEE-03-310 and several related compounds were subsequently granted to CeNeS Pharmaceuticals in 1999. CeNeS is currently investigating the drug's potential in the treatment of insomnia and alcohol dependency [340965], [382293], [401496],[416026]. A phase II, double-blind, placebo-controlled trial of CEE-03-310 demonstrated a dose-dependent enhancement of NREM sleep at the beginning of the night without any effects on the quantity of REM sleep [410739].