[N-Allyl-Dmt¹]-Endomorphins Are μ-Opioid Receptor Antagonists Lacking Inverse Agonist Properties

Abstract

ABSTRACT[N-Allyl-Dmt 1 ]-endomorphin-1 and -2 ([N-allyl-Dmt 1 ]-EM-1 and -2) are new selective -opioid receptor antagonists obtained by N-alkylation with an allyl group on the amino terminus of 2Ј,6Ј-dimethyl-L-tyrosine (Dmt) derivatives. To further characterize properties of these compounds, their intrinsic activities were assessed by functional guanosine 5Ј-O-(3-[35 S]thiotriphosphate) binding assays and forskolin-stimulated cyclic AMP accumulation in cell membranes obtained from vehicle, morphine, and ethanol-treated SK-N-SH cells and brain membranes isolated from naive and morphine-dependent mice; their mode of action was compared with naloxone or naltrexone, which both are standard nonspecific opioid-receptor antagonists. [N-Allyl- Dmt1 ]-EM-1 and -2 were neutral antagonists under all of the experimental conditions examined, in contrast to naloxone and naltrexone, which behave as neutral antagonists only in membranes from vehicle-treated cells and mice but act as inverse agonists in membranes from morphine-and ethanol-treated cells as well as morphine-treated mice. Both endomorphin analogs inhibited the naloxone-and naltrexone-elicited withdrawal syndromes from acute morphine dependence in mice. This suggests their potential therapeutic application in the treatment of drug addiction and alcohol abuse without the adverse effects observed with inverse agonist alkaloid-derived compounds that produce severe withdrawal symptoms.The -opioid receptor (MOP) is a key element in the neuronal reward pathway in the central nervous system, responsible for craving and addiction to various drugs, such as morphine and its derivatives, as well as alcohol and food (Di Chiara et al

The Relative Potency of Inverse Opioid Agonists and a Neutral Opioid Antagonist in Precipitated Withdrawal and Antagonism of Analgesia and Toxicity

“…Finally, Divin et al (2008) report that 6␤-naltrexol did not block withdrawal precipitated by the putative inverse agonist naltrexone in the mouse. The reason for this outcome is not clear, but there are several studies, including the present report, that have demonstrated that inverse agonist effects, including precipitated withdrawal, are inhibited by neutral antagonists such as 6␤-naltrexol (Raehal et al, 2005;Walker and Sterious, 2005;Marczak et al, 2007;Wang et al, 2007). Furthermore, in the present study 6␤-naltrexol was effective in inhibiting withdrawal in both morphine-and fentanyldependent mice, which suggests that this effect is likely to extend to dependence on other opioid agonists.…”

“…Studies strongly suggest that the commonly used opioid antagonists naloxone and naltrexone display negative efficacy and are therefore classified as inverse agonists (Costa and Herz, 1989;Wang et al, 2001;Marczak et al, 2007). Although all opioid antagonists are capable of reversing or blocking the effects of opioid agonists, only inverse agonists inhibit signaling of constitutively active opioid receptors (Wang et al, 2004;Sadée et al, 2005;Sirohi et al, 2007).…”

Effects of naltrexone and LY255582 on ethanol maintenance, seeking, and relapse responding by alcohol-preferring (P) rats

“…However, under certain conditions, NAL does exhibit inverse agonist activity. For example, NAL behaved as a neutral antagonist only in membranes from vehicle-treated cells and mice, but acted as an inverse agonist in membranes from morphine-and ethanol-treated cells in vitro, and morphine-treated mice in vivo (Marczak et al, 2007; Wang et al, 2001, 2007). Overall, it can be concluded that the conditions under which LY and NAL act as inverse agonists differ.…”

Engineering endomorphin drugs: state of the art

“…Since the existence of natural occurring opioid antagonists are unknown, the initial development of antagonists were formulated on the structural nucleus of morphine, which yielded naloxone [8] and naltrexone [9], among a large variety of compounds [10]; however, these morphinan-derived antagonists have numerous and often adverse side effects, such as withdrawal symptoms in the treatment of drug addiction and alcoholism due to suppression of the basal activity of opioid receptors [11], termed inverse agonism [12]. The unique sequence of the endomorphins, on the other hand, permitted judicious substitutions that provided not only more potent agonists, but also and importantly in our discussion on the attenuation of non-pain medical syndromes, the appearance of selective or mixed antagonists.…”