Synthesis and opioid activity of novel 6-ketolevorphanol derivatives.

Novel 6-ketolevorphanol analogs with diverse substitution patterns at ring C were synthesized and their binding affinities at the µ,δ and κ opioid receptors were investigated. The in vitro activity of the new analogs was then evaluated in the functional assay based on the electrically-stimulated contractions of the mouse ileum. It was shown that analogs with Δ7,8 bond had no significant potency at any of the opioid receptor types. In contrast, analogs with the saturated ring C were either potent κ agonist or antagonist depending on the absence or presence of the hydroxyl group in position 14.

Synthesis and characterization of thiazolo- and thiazinomorphinans and their intermediate products as novel opioid-active derivatives.

A new procedure was elaborated for the synthesis of potentially opioid-active thiazolo- and thiazinomorphinans. These derivatives and some intermediates related with the synthesis were tested in opioid receptor binding studies. Two compounds showed remarkable µ opioid activities and specificities. The ligand-stimulated [(35) S]GTPγS assays confirmed for both compounds the potent full agonist profile at the µ receptor and for the benzothiazinomorphinan derivative also the δ receptor full agonist character. The structures of these remarkably effective compounds were analyzed with the aid of computational chemistry calculations.

New 2-thioether-substituted apomorphines as potent and selective dopamine D2 receptor agonists.

A set of novel apomorphine derivatives were synthesized with diversely functionalized side chains in the proximity of position 2 of the aporphine skeleton. Amino and/or carboxylic functions were introduced to this region of the backbone to test their pharmacological effects. During the synthesis of 2-(S-3-mercaptopropionic acid)-derivative a heteroring-fused congener was also isolated. The structural elucidation confirmed that the formation of this product was in accordance with our previous observations on the reaction of thebaine (2) with thiosalycilic acid. All the novel apomorphine congeners 4a-g were neuropharmacologically characterized to discover their dopaminergic profiles. Two derivatives were identified as D(2) full agonists equipotent with apomorphine (1) having significantly increased D(2)/D(1) selectivity ratios.

Synthesis and opioid activity of novel 6-substituted-6-demethoxy-ethenomorphinans.

A set of novel 6-substituted orvinols was synthesized and pharmacologically characterized in order to explore the effect of the polarity and steric effects of these new moieties on the opioid activity. It was revealed that longer 6-O-alkyl chains led to increased agonistic activities, while the lack of C6-etheral oxygen gave rise to an antagonistic profile at the opioid receptors in the mouse ileum.

Synthesis and pharmacological evaluation of thiazole and isothiazole derived apomorphines.

We have presented the synthesis of novel thiazolo- and isothiazolo-apomorphines 12-17 resulting-in part-from an unexpected isomerization step occurred during the acid-catalyzed rearrangement of precursor thiazolo-morphinandienes 3-5. These 2,3-disubstituted apomorphines represent a new group of A-ring substituted aporphines. The receptor binding studies revealed that with the exception of two derivatives all the tested compounds have limited affinity for dopamine-receptor subtypes. Functional calcium assay for the most active isothiazolo-apomorphine showed higher affinities for D(1) and D(2L) subtypes. The docking of these ligands has been modelled to human D(2) and D(3 )receptors. On the basis of the predicted models, we identified an important cation-p interaction for the binding of isothiazolo-apomorphine 16.

Recent developments in the chemistry of thebaine and its transformation products as pharmacological targets.

The most practical synthetic routes to the preparation of as important pharmaceuticals as oxycodone, naloxone, naltrexone, nalbuphine and buprenorphine have utilized the alkaloid, thebaine, as a starting material. This review intends to focus on chemical transformations of morphinans which resulted in morphinandiene derivatives with well-established and novel pharmacological potencies. These chemical transformations were mainly associated with the formation and substitution of the unique diene structure of the ring C of the morphinan backbone.

Thiazole constrained analogues of the thevinones: synthesis and structure.

A simple synthesis of ring-constrained endoethenomorphinans possessing 2'-substituted thiazole ring 4-6 has been achieved by regio- and stereoselective Diels-Alder reaction of thiazolomorphinandienes 1-3 and methyl vinyl ketone in high yield (72, 64 and 87%, respectively). The structure of cycloaddition products was determined by high resolution mass spectrometry (HRMS), IR, 1D and 2D NMR techniques. Double-pulsed field gradient spin-echo-nOe and HMBC were found to be particularly powerful and indispensable tools in the exact structural elucidation of the presented new class of spatially constrained thevinones.

N-Substituted-2-alkyl- and 2-arylnorapomorphines: novel, highly active D2 agonists.

Two synthesis routes have been elaborated for the preparation of novel N-substituted-2-alkyl- and 2-arylnorapomorphines. The first one utilizes the traditional methodology of N-substitution of morphinans before acid-catalyzed rearrangements into aporphinoids, while our new approach involves the N-substitution directly on the aporphine backbone. The aimed compounds were obtained in similar overall yields in different synthesis routes and were investigated with respect to their binding affinities and activities to dopamine D(2) and D(1) receptors. These studies revealed remarkable affinity and selectivity of some compounds for D(2) over D(1) receptor subtypes. Partial or full agonist properties were confirmed for all tested compounds.

Synthesis and neuropharmacological characterization of 2-O-substituted apomorphines.

We have synthesized novel 2-O-substituted apomorphines with both different lengths of lipophilic alkyl chains and alkyl chains carrying free hydroxyl groups. Two bis-apomorphines formed as side products of the reactions with diols were isolated and characterized as well. The neuropharmacological profile of all these new compounds were investigated with respect to their binding affinities and activities to dopamine D(2) and D(1) receptors. The obtained data pointed to the fact that, in the examination of dopaminergic activities of 2-substituted apomorphines, the lipophilicity of the substituent is more important than its spatial parameters.

Synthesis and neuropharmacological evaluation of 2-aryl- and alkylapomorphines.

A novel synthesis has been elaborated for the pharmacologically remarkable 2-arylapomorphines described and characterized in the last few years. This new procedure contains two alternative synthetic routes and has allowed the preparation of several hitherto unknown compounds as well. The pharmacological profile of the previously published and the novel 2-alkyl- and arylapomorphines has been determined with the application of in vitro and in vivo techniques. For 2-phenyl- (2) and 2-(4-hydroxyphenyl)apomorphines (3) the superior dopamine agonist profile has been confirmed and for the novel compounds some remarkable results have been observed.

Synthesis and dopamine receptor binding of sulfur-containing aporphines.

We investigated acid-catalyzed rearrangement of thebaine 14 and its N-propyl analog 15 with methanesulfonic acid in the presence of the nucleophiles methanethiol and hydrogen sulfide. R(-)-2-methylthioapocodeine 16, R(-)-2-methylthioapomorphine 18, and their N-n-propyl analogs 17, 19 were obtained by rearrangement in the presence of methanethiol. However, with hydrogen sulfide, rearrangement of thebaine 14 and its N-n-propyl analog 15 produced sulfide-linked bis-aporphines 21-24 instead of expected R(-)-2-mercaptoapocodeines 12, 13 and R(-)-2-mercaptoapomorphines 10, 11. R(-)-2-Methylthio-N-n-propylnorapomorphine 19 had higher affinity (Ki = 3.7 nM) at D2 receptors in rat forebrain tissue than other novel 2-substituted sulfur-containing aporphines (Ki > or = 50 nM). Behavioral testing of the novel agents in rat indicated moderate locomotor arousal after systemic injection, and none after intragastric administration, indicating poor oral bioavailability.

Pharmacological characterization of ecstasy synthesis byproducts with recombinant human monoamine transporters.

Ecstasy samples often contain byproducts of the illegal, uncontrolled synthesis of N-methyl-3,4-methylenedioxy-amphetamine or 3,4-methylenedioxymethamphetamine (MDMA). MDMA and eight chemically defined byproducts of MDMA synthesis were investigated for their interaction with the primary sites of action of MDMA, namely the human plasmalemmal monamine transporters for norepinephrine, serotonin, and dopamine [(norepinephrine transporter (NET), serotonin transporter (SERT), and dopamine transporter (DAT)]. SK-N-MC neuroblastoma and human embryonic kidney cells stably transfected with the transporter cDNA were used for uptake and release experiments. Two of the eight compounds, 1,3-bis (3,4-methylenedioxyphenyl)-2-propanamine (12) and N-formyl-1,3-bis (3,4-methylenedioxyphenyl)-prop-2-yl-amine (13) had uptake inhibitory potencies with IC50 values in the low micromolar range similar to MDMA. Compounds with nitro instead of amino groups and a phenylethenyl instead of a phenylethyl structure or a formamide or acetamide modification had IC50 values beyond 100 microM. MDMA, 12, and 13 were examined for induction of carrier-mediated release by superfusion of transporter expressing cells preloaded with the metabolically inert transporter substrate [3H]1-methyl-4-phenylpyridinium. MDMA induced release mediated by NET, SERT, or DAT with EC50 values of 0.64, 1.12, and 3.24 microM, respectively. 12 weakly released from NET- and SERT-expressing cells with maximum effects less than one-tenth of that of MDMA and did not release from DAT cells. 13 had no releasing activity. 12 and 13 inhibited release induced by MDMA, and the concentration dependence of this effect correlated with their uptake inhibitory potency at the various transporters. These results do not support a neurotoxic potential of the examined ecstasy synthesis byproducts and provide interesting structure-activity relationships on the transporters.