Investigation On Narcotics And Polycyclic Morphinanes With Kappa Opioid "Address" Components

The researches on opioid analgesics have lasted for more than two centuries, whose history, painful but fantastic, was briefly reviewed in the first chapter. We have to make gains in pain since the researches on traditional opioids was discouraged by analgesic booming against novel potential targets and the reality of failure on R&D ofκopioid selective agonists from arylacetamides.A variety of non-peptidicκligands (e.g. morphine analogs, arylacetamides, arylpiperidines and other structures) were critically reviewed in the second chapter. We focused on some related parameters such as binding affinity, potency and efficacy ofκligands, as well as their SAR (Structure-Activity Relationships) analysis. Then the concepts of "message" and ""address" were introduced intoκopioid investigations, from which the key theme of this thesis was derived. That is. analgesics should specifically bind and activateκopioid receptor to exert their pain-relief functions, but need maintain gentle binding affinities toμorδopioid receptors, which should be helpful to overcome the unacceptable side-effects ofκopioid agonists such as dysphoria and psychoactive effects.In the third chapter two categories of polycyclic morphinanes, namely natrindole analogs and orvinols, were discussed in detail, where molecular modeling and 3D-QSAR analysis were carried out to explore the "message" and "address" components over the morphine skeleton. In addition to good results achieved, the "address" component ofκopioid ligands was suggested to consist of an agonistic type of "address" and an antagonistic type of "address". The former "address" interacts with Tyr312 residue (VII:03) ofκopioid receptor by hydrogen bonds or/and hydrophobic interactions, whereas the latter one forms a salt bridge with Glu297 (VI:23) of the receptor.Based on the enlightened suggestions proposed in Chapter Three, two series of compounds identified as polycyclic morphinanes were designed and prepared in the forth chapter and initial pharmacological assays were conducted.Considering the non-selective thebaine as the skeleton, potentialκ"address" components (e.g. aromatic, hydrogen donor/acceptor or basic groups) were introduced to find analgesic leads throughκopioid acting mechanisms. With nitrobenzaldehyde as the starting material, phenyl thebaine series were prepared successfully by knoevenagel condensation with malonic acid, followed by decarboxylation to afford nitrostyrenes, then thermal cycloaddition with thebaine, the reduction of nitro group, and the substitution of guanidine group. During the Diels-Alder reactions of thebaine with nitrostyrenes, unexpected 8α-adducts, which were not present in the adducts of other single substituted dienophiles, were elucidated and verified by X-ray crystallography techniques. Discussion on the formation mechanism of these side products provided more detailed insights to understand Diels-Alder reactions. Unlike phenyl thebaine series, synthesis forwarded to nepenthone series were tried and failed by thevinols or classical nepenthone preparations. New synthetic routes were schemed and performed in this thesis and they were further validated to be successful to obtain our target molecules on nepenthone series. Synthesis was initiated by Grignard reactions of nitrobenzaldehyde with Bromovinylmagnesium at low temperature, followed by Jones oxidation, then by thermal cycloaddition with thebaine to afford nitronepenthones. And the transformation of nitronepenthones to various substituted nepenthones were investigated by reduction of nitro group with hydrazine/Raney nickel, reduction of carbonyl group with potassium borohydride, Grignard reactions of carbonyl group with iodomethylmagnesium and substitution of guanidine group.Binding affinity assays were conducted on cloned opioid receptors. For phenyl thebaine series, although phenyl thebaine showed low binding profiles against opioid receptors, the binding toμopioid receptor was favored by introduction of 8a-phenyl group with electron demanding properties. The presence of amino group could enhance affinity toκreceptor, which was proposed to be mediated through hydrogen donor/acceptor interactions other than salt bridge interactions. Furthermore, the p-amino substitution was critically required forκagonistic activity. The site onκreceptor involved in this interaction was suggested to be Tyr312 (VII:03). But for nepenthone series, different SARs were observed. The prototype compounds of this series, thevinone and nepenthone, retained someμopioid affinities. Nitronepenthones showed slightly increased binding toμandκreceptors. However, the affinities were almost abandoned by the introduction of amino group except for 2-amino nepenthone. In case of 2-amino nepenthone, the negative electronic effects were neutralized by the interaction of amino group with corresponding site onμandκopioid receptor. Nepenthols showed increasedκbut reducedμreceptor binding affinities as a result of formation of 19S-configuration and additional hydroxyl group. Similar to amino nepenthones, amino nepenthols abandonedκaffinities with slightly increasedμaffinities except for 2-amino nepenthols.Based on the results of RVD assays and rodent antinociceptive models in vivo, the para position of amino group was essential forκagonist potency and thus considered as aκ"address" component in phenyl thebaine series. LQ004C (16) contained this subunit was a kappa opioid agonist with similar activities to the marketed butorphanol which was believed to exert its analgesic potency throughκopioid receptor in RVD assays. Furthermore, LQ004C (16) was found to be an analgesic in vivo, with 10 less fold than butorphanol. And this compound showed desirable profiles for further investigations.In Chapter Five, the conformation of a marketed analgesic meptazinol. categorized as 3-aryl azepines, was investigated thoroughly, because its mixed pharmacological nature was still confusing to date. Our study began with an unexpected phenomenon observed on NMR spectra of meptazinol hydrochloride, followed by elucidation of different conformers in (+)-meptazinol hydrochloride present in solution, and then the mechanism of formation was discussed in detail. The resolved conformers were used for structural comparisons with the known opioid pharmacophores, from which (+)-meptazinol was suggested to be an opioid with different analgesic pharmacophore. The investigation provided heuristic insights for novel analgesic R&D from opioids.As the experimental part of Chapter Four, Chapter Six deal with more than forty five intermediates and target molecules, among which twenty eight compounds were novel. Detailed processes in organic synthesis and physiochemical properties were provided, as well as the data obtained from IR, NMR and MS spectra. Furthermore, the structures of LQ003A and LQ003B from phenyl thebaine series were also examined by X-ray crystallography.