Abstract
Opiates are still the most effective and widely used treatments for acute and chronic pain. However, the problems associated with morphine and other standard opioid analgesics severely limit their effectiveness in the clinic. PPL-101 and PPL-103 derived from morphine and morphinan ring systems contain a chiral N-substituent, which confers it with a unique combination of high-binding affinities and partial agonist activities at mu, delta, and kappa opioid receptors, leading to unique in vivo pharmacology compared to other conventional opioids. Acute antinociceptive and reward acquisition of PPL-101 and PPL-103 were assessed in mice using the tail flick assay and conditioned place preference (CPP) paradigm, respectively. The reinforcing effects of these compounds were assessed in rats using the self-administration paradigm. In mice, PPL-101 and PPL-103 produced antinociception reaching maximal effects that were equivalent to morphine at approximately 1/3 and 1/10 of morphine’s dose, respectively. PPL-101-induced antinociception was attenuated following pretreatment with the kappa antagonist JDTic, but not the mu opioid antagonist beta-FNA. In mice, PPL-101 and PPL-103 produced dose-dependent decreases in activity, similar to other kappa agonists; however, they did not produce conditioned place aversion, and in fact elicited a trend toward CPP. In rats, neither PPL-101 nor PPL-103 were self-administered when substituted for morphine and PPL-101 attenuated morphine self-administration, when administered systemically prior to the self-administration session. Collectively, these results indicate that mixed opioid receptor partial agonists can produce potent antinociceptive activity with a lack of aversion in mice and without being self-administered in rats. Compounds with this profile could be superior analgesics with greatly reduced addiction liability and fewer side-effects compared to traditional opiates.
Highlights
It is well known that activation of the different opioid receptors induces different pharmacological actions
The α-methyl-cyclopropylmethyl (α-methyl-CPM) moiety found in PPL-101 and PPL-103, as well as CPM found in cyclazocine and buprenorphine, induces high affinity for mu, kappa, and delta opioid receptors, unlike their N-CH3 counterparts, such as morphine, which have considerable selectivity for the mu receptors [Table 1; and see Ref. [16]]
The in vitro functional activity, as determined by [35S]GTPγS binding, is affected by the N-substitution, as the α-methyl-CPM moiety induces a change in efficacy, so that PPL-101 and PPL-103 have low efficacy at mu and delta receptors and higher partial agonist activity at kappa receptors (Table 2)
Summary
It is well known that activation of the different opioid receptors induces different pharmacological actions. Mu receptor activation induces antinociception, along with a decrease in respiration and gut motility, and significant abuse liability [1, 2]. Kappa receptor activation induces antinociception but with reduced respiratory depression and reduced inhibition of gut motility [2,3,4]. With respect to potential for abuse, kappa receptor agonists often induce dysphoria and are generally considered not to have abuse liability [5, 6]. The ramifications of delta receptor activation are less clear. In regard to reward/reinforcement, the findings with delta agonists are mixed, with some evidence pointing to delta-mediated reward, while other evidence suggests that even selective delta agonists require mu receptors to generate reinforcing properties [10,11,12]
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