Fuying Li

Synthesis Study on Marmycin A: Preparation of the C3'-Desmethyl Analogues

Total synthesis of natural product marmycin A was studied. An expeditious synthetic strategy for the key fragment 8-amino-3-methylbenz[a]anthraquinone (1) was established with decarboxylative alkylation, Pd(OAc)(2)-catalyzed cyclization, aromatization, and C-N coupling as the key steps. However, final assembly of marmycin A was hampered by the failure to obtain the carbohydrate fragment 2. Instead, a small library of desmethyl analogues of marmycin A was prepared in moderate yields by using the InBr(3)-catalyzed C- and N-glycosidation reaction. The absolute configuration of these compounds was confirmed by comparison of their spectroscopic data with that reported for marmycin A, and by X-ray analysis.

Pharmacological Characterization of ATPM [(-)-3-Aminothiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a Novel Mixed κ-Agonist and μ-Agonist/-Antagonist That Attenuates Morphine Antinociceptive Tolerance and Heroin Self-Administration Behavior

ATPM [(-)-3-amino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] was found to have mixed κ- and μ-opioid activity and identified to act as a full κ-agonist and a partial μ-agonist by in vitro binding assays. The present study was undertaken to characterize its in vivo effects on morphine antinociceptive tolerance in mice and heroin self-administration in rats. ATPM was demonstrated to yield more potent antinociceptive effects than (-)U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide). It was further found that the antinociceptive effects of ATPM were mediated by κ- and μ-, but not δ-opioid, receptors. In addition to its agonist profile on the μ-receptor, ATPM also acted as a μ-antagonist, as measured by its inhibition of morphine-induced antinociception. It is more important that ATPM had a greater ratio of the ED50 value of sedation to that of antinociception than (-)U50,488 (11.8 versus 3.7), indicative of a less sedative effect than (-)U50,488H. In addition, ATPM showed less potential to develop antinociceptive tolerance relative to (-)U50,488H and morphine. Moreover, it dose-dependently inhibited morphine-induced antinociceptive tolerance. Furthermore, it was found that chronic treatment of rats for 8 consecutive days with ATPM (0.5 mg/kg s.c.) produced sustained decreases in heroin self-administration. (-)U50,488H (2 mg/kg s.c.) also produced similar inhibitory effect. Taken together, our findings demonstrated that ATPM, a novel mixed κ-agonist and μ-agonist/-antagonist, could inhibit morphine-induced antinociceptive tolerance, with less potential to develop tolerance and reduce heroin self-administration with less sedative effect. κ-Agonists with some μ-activity appear to offer some advantages over selective κ-agonists for the treatment of heroin abuse.

Synthesis and opioid receptor activity of indolopropellanes

A series of skeletal rearranged indolomorphinans 7a-d were obtained by N-demethylation of 3-methoxy-N-methyl-14-hydroxymorphinan-6-one 12 followed by N-realkylation, reduction and Fischer indole cyclization. The structure of the novel skeleton was confirmed by X-ray analysis. These new indoles displayed moderate binding affinity and selectivity at the mu receptor, with compound 7b showing the highest affinity at this receptor with a K(i) value of 40nM, and 6- and 25-fold selectivity against delta and kappa receptors, respectively. Function assays showed that indolopropellanes 7b and 7c possessed full agonistic activity at all the opioid receptors indicating a different interaction model existed.

Effects of ATPM-ET, a novel κ agonist with partial μ activity, on physical dependence and behavior sensitization in mice

Aim:To investigate the effects of ATPM-ET [(−)-3-N-Ethylaminothiazolo [5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] on physical dependence and behavioral sensitization to morphine in mice.Methods:The pharmacological profile of ATPM-ET was characterized using competitive binding and GTPγS binding assays. We then examined the antinociceptive effects of ATPM-ET in the hot plate test. Morphine dependence assay and behavioral sensitization assay were used to determine the effect of ATPM-ET on physical dependence and behavior sensitization to morphine in mice.Results:The binding assay indicated that ATPM-ET ATPM-ET exhibited a high affinity to both κ- and μ-opioid receptors with Ki values of 0.15 nmol/L and 4.7 nmol/L, respectively, indicating it was a full κ-opioid receptor agonist and a partial μ-opioid receptor agonist. In the hot plate test, ATPM-ET produced a dose-dependent antinociceptive effect, with an ED50 value of 2.68 (2.34–3.07) mg/kg. Administration of ATPM-ET (1 and 2 mg/kg, sc) prior to naloxone (3.0 mg/kg, sc) injection significantly inhibited withdrawal jumping of mice. In addition, ATPM-ET (1 and 2 mg/kg, sc) also showed a trend toward decreasing morphine withdrawal-induced weight loss. ATPM-ET (1.5 and 3 mg/kg, sc) 15 min before the morphine challenge significantly inhibited the morphine-induced behavior sensitization (P<0.05).Conclusion:ATPM-ET may have potential as a therapeutic agent for the treatment of drug abuse.

Pharmacological characterization and therapeutic potential for the treatment of opioid abuse with ATPM-ET, an N-ethyl substituted aminothiazolomorphinan with κ agonist and μ agonist/antagonist activity

We previously reported that the κ agonists with mixed μ activity could attenuate heroin self-administration with less potential to develop tolerance. The present study further investigated the effects of (-)-3-N-Ethylamino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride (ATPM-ET), a κ agonist and μ agonist/antagonist, on the acquisition and reinstatement of morphine-induced conditioned place preference (CPP), heroin self-administration and heroin-primed reinstatement of drug-seeking behavior. We found that ATPM-ET produced a longer duration of potent antinociceptive effects with less side effect of sedation. More importantly, ATPM-ET attenuated the acquisition of morphine-induced CPP, without affecting the reinstatement of morphine CPP. Furthermore, ATPM-ET significantly inhibited heroin self-administration and the reinstatement of heroin primed drug-seeking behavior. Taken together, ATPM-ET, a novel κ agonist and μ agonist/antagonist may have utility for the treatment of drug dependence.

Synthesis and SAR Study of Opioid Receptor Ligands: Mono- and Bis-Indolomorphinans

Mono‐ and bis‐indolomorphinans were synthesized through a multi‐step synthetic approach from the alkaloid, thebaine, to further explore the C‐ring SAR (structure‐activity relationship) of morphinan scaffold. Both mono‐indoles displayed good binding affinity and selectivity for the δ receptor, with compound 6b possessed the highest Ki value of 1.45 nm at this receptor. Bisindolomorphinans 7a,b did not have appreciable affinity for both δ and κ receptors, but moderate binding at the μ receptor was observed. Functional assays indicated that the newly synthesized mono‐indole 6b was δ‐agonist, opposite to the δ‐antagonist profile of naltrindole. Bisindoles 7a,b were μ‐agonists. This work further confirms that the phenol component in opioids is essential for higher binding to the opioid receptors. The different binding ability, receptor selectivity, and the functional activity profiles of naltrindole 2, monoindole 6b, and bisindole 7b clearly indicated that they interact with the opioid receptors in different modes.

[6,7]-Heterocycle-Fused 14-Hydroxymorphinan Derivatives: Design, Synthesis, and Opioid Receptor Activity†

A series of new 14‐hydroxymorphinan analogues with a thiazole or imidazo[2,1‐b]thiazole fragment as the heterocyclic function fused to ring C were designed and synthesized. These compounds can be viewed as the result of a direct modification at ring C of the 14‐hydroxymorphinan scaffold. Among these compounds, three were identified as having potent binding affinity (∼1 nM) at both κ and μ receptors, and acting as agonists at κ and partial agonists or antagonists at μ receptors. In view of the promising results from studies on compounds with mixed κ and μ receptor activities, these new compounds warrant further investigation.