NE-100, a novel sigma receptor ligand: In vivo tests

Novel sigma (σ) receptor agonists produce antidepressant-like effects in mice

“…Using the forced swim and tail suspension tests, earlier investigators have demonstrated that σ receptors agonists such as igmesine, SA4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine), (+)-SKF-10,047, di-otolylguanidine (DTG) and (+)-pentazocine produce antidepressant-like actions in rodents Rogoz, 1997, 2002;Ukai et la., 1998;Urani et al, 2001). A role for σ receptors in these effects was further confirmed by the ability of σ receptor antagonists such as BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-Nmethyl-2-(dimethylamino)ethylamine) and phenyl]ethylamine) to attenuate the antidepressant-like actions of the agonists (Okuyama et al, 1993;Matsumoto et al, 1995;Kobayashi et al, 1996;Urani et al, 2001). In humans, the high affinity σ receptor agonist igmesine hydrochloride yielded promising results in Phase II clinical trials.…”

Differentiation of σ ligand‐activated receptor subtypes that modulate NMDA‐evoked [3H]‐noradrenaline release in rat hippocampal slices

“…Figure 1 shows that haloperidol (300 nM) was very effective in preventing the potentiating effect of (+ )-pentazocine (100-300 nM; Figure ( Figures 5 and 6) and shifted the response curve of BD-737 to the right ( Figure 5). Reduced haloperidol, BD-1008 and NE-100, which all exhibit selectivity and high affinity for a sites Bowen et al, 1990;Okuyama et al, 1993;Klein et al, 1994) concentration-dependently (10 nm to 1 gM) antagonised the BD-737(100 nM)-induced effect ( Figure 6). …”

“…Although the different profiles of action of these specific a drugs were most likely due to methodological differences between protocols, the observation by Gonzalez-Alvear & Werling (1995) supported the notion that (+)-pentazocine and BD-737, and DTG were acting on a1 and a2 receptors, respectively. They also showed that the BD-737-induced modulation of the (BD-737 and BD-738;de Costa et al, 1990;Bowen et al, 1992), N-[2-(3,4- 1993), N,N-dipropyl -2 -[4-methoxy-3-(21 lphenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100) (Okuyama et al, 1993) and 4 -(4 -chlorophenyl) -a -4 -fluorophenyl) -4 -hydroxy -1-piperidinebutanol (reduced haloperidol; Bowen et al, 1990; Klein et al, 1994) has been proposed to behave as an antagonist in some systems and as an agonist in others Klein et al, 1994 Fink et al, 1989). At the end of the experiments, the hippocampal slices were collected and solubilised in 0.5 ml of Soluene' 350 (Packard Instruments, Rungis, France) and the radioactivity in the slices and superfusate samples was determined by liquid scintillation spectrometry (Packard Tris-Carb 4660).…”

“…Reduced haloperidol [4-(4-chlorophenyl NE-100 is another high affinity and specific a ligand (Okuyama et al, 1993;Chaki et al, 1994). Since by itself, NE-100 has been shown to be devoid of effect in conditioned avoidance response in rats, head-weaving behaviour in dogs, attention capacity in monkeys but dose-dependently suppresses the effects of phencyclidine in the latter models, Okuyama et al (1994) proposed that it behaves as a potent al antagonist.…”

“…Since by itself, NE-100 has been shown to be devoid of effect in conditioned avoidance response in rats, head-weaving behaviour in dogs, attention capacity in monkeys but dose-dependently suppresses the effects of phencyclidine in the latter models, Okuyama et al (1994) proposed that it behaves as a potent al antagonist. Interestingly, BD-1008 and NE-100 have been shown to act similarly and equipotently as a antagonists in both the NMDA-evoked release of [3H]-dopamine from striatal slices (Gonzales-Alvear & Werling, 1994) and the headweaving behaviour produced by the a agonist (+ )-SKF-10047 (Okuyama et al, 1993;1994). In our model, NE-100 (> 30 nM) antagonized BD-737(100 nM)-induced potentiation of NMDA-evoked release of [3H]-NA (Figure 6), whereas it failed to reverse, even at micromolar concentrations, DTG-induced inhibition of the NMDA-evoked release of [3H]-NA (Figure 3).…”