Effects of SR 142801, the first non-peptide NK3 receptor antagonist on cardiovascular and behavioural responses to senktide in guinea-pigs

Roccon, Alain; D, Marchionni; Nisato, Dino

doi:10.1016/1043-6618(95)87024-5

Cited by 1 publication

(1 citation statement)

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“…Accordingly, antagonism of dysregulated SP activity at the NK 1 receptor, the only neurokinin receptor known to be clearly expressed in human brain to date, might provide a novel mechanism for antidepressant and/or anxiolytic effects. Preclinical behavioral pharmacology studies with tachykinin NK 1 receptor antagonists (Cheeta et al, 2001;Cutler, 1994;Regoli et al, 1994;Roccon et al, 1995;Vassout et al, 1994) have been complicated by species variants in receptor pharmacology. However, behavioral studies (Kramer et al, 1998) utilizing brain-penetrant NK 1 antagonists in a species (guinea pig) with NK 1 pharmacology similar to that seen in humans provided evidence that selective blockade of the NK 1 receptor was associated with an antidepressant-like profile.…”

Section: Introductionmentioning

confidence: 99%

Demonstration of the Efficacy and Safety of a Novel Substance P (NK1) Receptor Antagonist in Major Depression

Kramer

Winokur

Kelsey

et al. 2003

Neuropsychopharmacol

243

140

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The efficacy and safety of a selective NK 1 antagonist, L-759274, was investigated in outpatients with diagnosis of major depressive disorder with melancholic features, following evidence obtained with the novel compound aprepitant that Substance P (NK 1 ) antagonists may provide a unique mechanism of antidepressant activity. A randomized, double-blind placebo-controlled study was carried out. Patients, male or female, aged 18-60, scoring X25 points on total of first 17 items of 21-item Hamilton Depression Scale (HAMD), and scoring X4 (moderately ill) on Clinical Global Impressions-Severity Scale were randomized to oral L-759274 40 mg daily (n ¼ 66) or placebo (n ¼ 62) for 6 weeks. For patients receiving L-759274, improvement (mean decrease from baseline) in HAMD-17 total score was 10.7 points, compared with a mean 7.8 point improvement in patients receiving placebo (po0.009). Mean scores for item 1 of HAMD-17 (depressed mood) also improved to a greater extent in the active group compared with the placebo group (0.3 points, po0.058). Compared with placebo, mean scores on Clinical Global Impressions-Improvement Scale improved significantly by the end of the trial (p ¼ 0.009). L-759274 was generally safe and well-tolerated. The incidence of sexual side effects was on par with that observed in patients receiving placebo, and the incidences of gastrointestinal effects were low. Antidepressant actions have now been observed with two different highly selective NK 1 antagonists (aprepitant and L-759274). NK 1 antagonism is a replicated and generally welltolerated antidepressant mechanism.

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