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.

01 Feb 2002·Current opinion in investigational drugs (London, England : 2000)

CEE-03-310 CeNeS pharmaceuticals.

Review

Author: Eder, Derek N

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].

01 May 1998·Journal of Endocrinological InvestigationQ2 · MEDICINE

Lack of effect of the dopamine D1 antagonist, NNC 01-0687, on unstimulated and stimulated release of anterior pituitary hormones in males

Q2 · MEDICINE

Article

Author: O Koldkjaer ; M Andersen ; J Hangaard ; C Hagen ; E Grodum

Dopamine in humans inhibits the secretion of luteinizing hormone (LH), follicular stimulating hormone (FSH), thyroid stimulating hormone (TSH) and prolactin (PRL), and is a stimulator of growth hormone (GH) secretion. Dopamine-D1 receptor stimulation with fenoldopam increases basal PRL levels, suppresses TSH, and increases gonadotropin releasing hormone (LHRH) induced LH release. We have investigated the effect of a dopamine D1-receptor antagonist, NNC 01-0687, on the secretion of anterior pituitary hormones. In 8 healthy males NNC 01-0687 and placebo were administered orally in a double-blind placebo controlled cross-over study for three days with a wash-out period of 14 days. Hormonal responses (PRL, LH, FSH, GH, TSH, thyroid hormones and testosterone), unstimulated and LHRH/TRH stimulated, were studied on days 1 and 3. No significant difference (p > 0.05) between placebo and active periods was found neither in unstimulated nor in stimulated hormone concentrations expressed in absolute values, percent change of before, incremental values and area under the curve. These results suggest that the neuronal DA-D1 activity is not activated during basal conditions in healthy male subjects.

100 Deals associated with ADX-10061

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Tobacco Use Disorder	Phase 2	GB	CeNeS Pharmaceuticals Plc	23 Dec 2004
Tobacco Use Disorder	Phase 2	-	Novo Nordisk A/S	23 Dec 2004
Tobacco Use Disorder	Phase 2	US	Addex Therapeutics Ltd.	23 Dec 2004
Sleep Initiation and Maintenance Disorders	Phase 2	-	CeNeS Pharmaceuticals Plc	02 Feb 2002
Sleep Initiation and Maintenance Disorders	Phase 2	-	Novo Nordisk A/S	02 Feb 2002
Schizophrenia	Phase 2	DK	Novo Nordisk A/S	-

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