δ-Opioid Agonists: Differential Efficacy and Potency of SNC80, Its 3-OH (SNC86) and 3-Desoxy (SNC162) Derivatives in Sprague-Dawley Rats

Abstract

The diarylpiperazine ␦-opioid agonist SNC80 [(ϩ)-4-[(␣R)-␣-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide] producesconvulsions, antidepressant-like effects, and locomotor stimulation in rats. The present study compared the behavioral effects in Sprague-Dawley rats of SNC80 with its two derivatives,which differ by one functional group located in the 3-position of the benzylic ring. In behavioral measures, these three compounds demonstrated a rank order of potency and efficacy; SNC86 was the most potent and efficacious followed by SNC80 and then SNC162. In vitro, these compounds stimulated guanosine 5Ј-O-(3-[35 S]thio)triphosphate ([ 35 S]GTP␥S) binding in the caudate putamen of coronal brain slices from drug-naive rats as measured by in vitro autoradiography. In [ 35 S]GTP␥S binding studies, SNC86 seemed to be a full agonist at the ␦-opioid receptor; however, SNC162 demonstrated reduced stimulation compared with SNC86, consistent with partial agonist activity. Although SNC80 was not fully efficacious in [ 35 S]GTP␥S autoradiography studies, it produced behavioral effects similar to those observed with SNC86, suggesting that the behavioral effects of SNC80 may be produced by its 3-hydroxy metabolite.Nonpeptidic ␦-opioid agonists produce a number of different behavioral effects. They produce convulsions in mice (Comer et al., 1993;Hong et al., 1998), rats (Broom et al., 2002a,b), and monkeys (Dykstra et al., 1993;Negus et al., 1994;Pakarinen et al., 1995); stimulate locomotor activity in rats (Spina et al., 1998;Fraser et al., 2000;Broom et al., 2002a); produce antinociception in mice (Hong et al., 1998); and maintain discriminative control of behavior in rats (Stevenson et al., 2002) and monkeys (Dykstra et al., 1993;Negus et al., 1994;Pakarinen et al., 1995). In addition, recent studies reported that nonpeptidic, ␦-opioid agonists demonstrated antidepressant-like effects in the forced swim test in rats (Broom et al., 2002a,b), and these compounds produced a greater magnitude of effect compared with known antidepressants such as desipramine and fluoxetine (Broom et al., 2002a). The antidepressant-like effects of the nonpeptidic ␦-opioid agonists were mediated through the ␦-opioid receptor, because these effects were blocked by the selective ␦-opioid antagonist naltrindole.Behavioral effects mediated by the ␦-opioid receptor have been most thoroughly studied with the class of nonpeptidic ␦-opioid receptor agonists known as the piperazinyl benzamides (SNC80 derivatives); however, few studies have compared the behavioral effects of these compounds within a given behavioral paradigm. Existing comparisons with SNC80 derivatives have only been made in drug discrimination paradigms in rats (Stevenson et al., 2002) and monkeys (Negus et al., 1998;Brandt et al., 1999). In addition to in vivo studies, these compounds have been compared in terms of

Essential role of mu opioid receptor in the regulation of delta opioid receptor–mediated antihyperalgesia

“…In rodents, deltorphin analogs and other DOR-selective agonists can interfere with motor functions (Longoni et al, 1991, Miaskowski et al, 1991, Negri et al, 1991, Spina et al, 1998, Fraser et al, 2000b, Broom et al, 2002, Jutkiewicz et al, 2004. In the present study, we observed that intrathecal administration of deltorphin II induced a rapid, but transient inhibition of motor capacities, an effect mimicked with SNC80 and reversed by the deltaselective antagonist naltrindole.…”

Separation of the convulsions and antidepressant-like effects produced by the delta-opioid agonist SNC80 in rats

“…4a), only one (17%) out of six rats convulsed with 10 mg kg −1 IV SNC80. All convulsions produced by slow infusions appeared similar to typical delta-opioid receptor-mediated convulsions (Broom et al 2002a;Jutkiewicz et al 2004). The dose-effect curve for convulsions was shifted to the right by increasing the duration of i.v.…”

“…Thus, minimizing the undesirable convulsive effects while retaining the antidepressant-like properties appears feasible. In particular, the latency to convulsion shortens with increasing the dose of agonist (Broom et al 2002a) and with different routes of administration (Jutkiewicz et al 2004), indicating that the speed with which drug enters the circulation and/or the central nervous system (CNS) may play a role in delta-opioid-mediated convulsions. These preliminary data suggested that it might be possible to alter the time to onset of convulsion and, possibly, other characteristics of this behavior.…”

“…Similarly, increasing levels of endogenous delta-opioid peptides with enkephalinase inhibitors such as RB101 revealed antidepressant-like effects in models of depression in mice and rats (Baamonde et al 1992;Tejedor-Real et al 1998). More recently, the nonpeptidic delta-opioid agonists SNC80 and (+)BW373U86 displayed naltrindole (NTI)-sensitive antidepressant-like properties in the forced swim test in rats (e.g., Broom et al 2002a;Jutkiewicz et al 2004). Overall, these findings suggest that activation of delta-opioid receptors may have therapeutic potential to treat depression.…”

NIH 11082 produces anti-depressant-like activity in the mouse tail-suspension test through a delta-opioid receptor mechanism of action

“…Similarly, increasing levels of endogenous delta-opioid peptides with enkephalinase inhibitors such as RB101 revealed antidepressant-like effects in both mice and rats (Baamonde et al, 1992;Tejedor-Real et al, 1998). In addition, the nonpeptidic delta-opioid receptor agonists SNC80 ( (+)-4-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1piperazinyl)-3-methoxybenzyl)N,N-diethylbenzamide) and (+)BW373U86 ((+)-4-[(alpha-R*)-alpha-[(2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl]-N,Ndiethylbenzamide) to rats elicited naltrindole-sensitive antidepressant-like properties, as assessed in the forced swim test (Broom et al, 2002a;Jutkiewicz et al, 2004;Jutkiewicz et al, 2005). Conversely, chronic administration of the potent, nonselective opioid receptor antagonist naltrexone to humans induced a self-reported mental depression in a placebocontrolled open study (Hollister et al, 1981), suggesting a general role for opioid systems in depression.…”