Aporphine Analogues Research Articles

Cytotoxic activities of alkaloid constituents from the climbing stems and rhizomes of Sinomenium acutum against cancer stem cells.

From the methanolic extract of the climbing stems and rhizomes of Sinomenium acutum, two new aporphine analogues, acutumalkaloids I and II, were isolated together with fifteen known compounds including lysicamine. The chemical structures of the isolated new compounds were elucidated based on chemical/physicochemical evidence such as NMR and MS spectra. For acutumalkaloids I and II, the absolute configurations were established by comparison of experimental and predicted electronic circular dichroism (ECD) data. We compared anti-proliferative activities of isolated compounds with reported naturally occurring Wnt/β-catenin pathway inhibitor, nuciferine. Among the isolated compounds, we found lysicamine have anti-proliferative activity against both of HT-29 human colon cancer cell line and its cancer stem cells (CSCs). The IC50 values of lysicamine against non-CSCs and its CSCs were lower than that of nuciferine. In addition, the results of western blotting analysis suggested that lysicamine inhibited the expression of Wnt/β-catenin pathway target protein such as survivin. These results suggested that lysicamine show cytotoxic activity via inhibition of Wnt/β-catenin pathway.

Structural optimizations and bioevaluation of N-H aporphine analogues as Gq-biased and selective serotonin 5-HT2C receptor agonists

The concept of subtype selectivity and functional bias has recently reshaped current GPCR drug discovery for G protein-coupled receptors. A series of new N-H aporphines with A-ring modifications have been synthesized, and their efficacy on 5-HT2 receptor activation was evaluated. SAR analysis led to the discovery of several more potent and selective 5-HT2C receptor agonists (e.g., 11b and 11f) with low nanomolar activity. Molecular docking analysis of this series of aporphines was in accordance with our SAR results. The functional selectivity of specific compounds was tested via both Gq-mediated calcium flux and β-arrestin recruitment assays, which revealed that these compounds exhibited no β-arrestin recruitment activity. Further ADMET study combined with behavioral assessment using a methamphetamine-induced hyperactivity model identified compound 11b and 11f possessing promising drug-like profiles and having antipsychotic potential. These agonists with an exclusive bias toward Gq signaling may serve as valuable pharmacological probes to facilitate the elucidation of therapeutically relevant 5-HT2C signaling pathways and the development of alternative antipsychotic medications.

Synthesis of Aporphine Analogues via Palladium-Catalyzed Intramolecular Aryl–Aryl Dehydrogenative Coupling

Reported herein is an intramolecular dehydrogenative coupling of two inert aryl C-H bonds for the synthesis of aporphine analogues. The process represents a novel tool for the preparation of aporphines via palladiun-catalyzed C-H bond activation. The present reaction is compatible with various functional groups, and the coupling products have been further applied for the synthesis of natural products aporphine and zenkerine.

Identification of Novel 1-O-Substituted Aporphine Analogues as Potent 5-HT2C Receptor Agonists.

The 5-HT2C receptor has emerged as a promising target in the treatment of a variety of central nervous system disorders. We have first identified aporphines as a new class of 5-HT2C receptor agonists. Structure-activity relationship results indicate that the aporphine core may be required for 5-HT2C receptor activity, and substitutions at its C1 position are important for 5-HT2C receptor activity. Our efforts to optimize our hit 15781 lead to the identification of the highly potent and selective 5-HT2C agonist 18b (MQ02-439) with an EC50 value of 104 nM and weak antagonism at the 5-HT2A and 5-HT2B receptors. The findings may serve as good starting points for the development of more potent and selective 5-HT2C agonists as valuable pharmacological tools or potential drug candidates.

Discovery of Aporphine Analogues as Potential Antiplatelet and Antioxidant Agents: Design, Synthesis, Structure-Activity Relationships, Biological Evaluations, and in silico Molecular Docking Studies.

To explore the potential of aporphine alkaloids, a novel series of functionalized aporphine analogues with alkoxy (OCH3 , OC2 H5 , OC3 H7 ) functional groups at C1/C2 of ring A and an acyl (COCH3 and COPh) or phenylsulfonyl (SO2 Ph and SO2 C6 H4 -3-CH3 ) functionality at the N6 position of ring B of the aporphine scaffold were synthesized and evaluated for their arachidonic acid (AA)-induced antiplatelet aggregation inhibitory activity and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical-scavenging antioxidant activity, with acetylsalicylic acid and ascorbic acid as standard references, respectively. The preliminary structure-activity relationship related to AA-induced platelet aggregation inhibitory activity results showed that the aporphine analogues 1-[1,2,9,10-tetramethoxy-6a,7-dihydro-4H-dibenzo[de,g]quinolin-6(5H)-yl]ethanone and 1-[2-(benzyloxy)-1,9,10-trimethoxy-6a,7-dihydro-4H-dibenzo[de,g]quinolin-6(5H)-yl]ethanone to be the best compounds of the series. Moreover, the DPPH free-radical-scavenging antioxidant activity results demonstrated that the aporphine analogues 1,2,9,10-tetramethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, 2-ethoxy-1,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, 1-ethoxy-2,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, 2,9,10-trimethoxy-6-(methylsulfonyl)-1-propoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, and 1-(benzyloxy)-2,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline were the best compounds of the series. Moreover, in silico molecular docking simulation studies of the active analogues were also performed.

Identification of N-Propylnoraporphin-11-yl 5-(1,2-Dithiolan-3-yl)pentanoate as a New Anti-Parkinson's Agent Possessing a Dopamine D2 and Serotonin 5-HT1A Dual-Agonist Profile

A series of new aporphine analogues (aporlogues) were synthesized bearing a C-, N-, or O-linkage at the C11 position. Lipoic ester (-)-15 was identified as a full agonist at the dopamine D(2) and serotonin 5-HT(1A) receptors with K(i) values of 174 and 66 nM, respectively. It elicited antiparkinsonian action on Parkinsin's disease (PD) rats with minor dyskinesia. Chronic use of (-)-15 reduced L-DOPA-induced dyskinesia (LID) without attenuating the antiparkinsonian effect. These results suggest that 5-HT(1A) and D(2) dual-receptor agonist (-)-15 may present a novel candidate drug in the treatment of PD and LID.

Further SAR study on 11-O-substituted aporphine analogues: Identification of highly potent dopamine D3 receptor ligands

A series of new aporphine analogues (aporlogues) were prepared from appropriate aporphine precursors and arylpiperazines using the Click reaction protocol. These compounds displayed good to high affinity at the D3 receptor, low or no affinity at the D1 and D2 receptors. Compounds 7f and 11c stood out as the most potent at the D3 receptor among our newly synthesized aporlogues with Ki values of 2.67 and 1.14nM, respectively. Further assay at the 5-HT1A receptor revealed that aporlogues 7f and 11c also showed high affinity at this receptor with Ki values of 9.68 and 7.59nM, respectively. They were 3.6- and 6.6-fold more potent at the D3 over 5-HT1A receptors. Such D3/5-HT1A dual property of these compounds may be useful in the treatment of several brain disorders.

Cytotoxic Aporphine Alkaloids fromOcotea acutifolia

Two new aporphinoid alkaloids, (+)-6 S-ocoteine N-oxide and (+)-norocoxylonine, were isolated from the leaves and trunk bark of OCOTEA ACUTIFOLIA (Lauraceae) along with thirteen aporphine analogues, one morphinan alkaloid, and one flavonoid. The aporphine alkaloids (+)-thalicsimidine and (+)-neolitsine are reported for the first time for the genus OCOTEA. The structures of all compounds were established on the basis of 1D- and 2D-NMR spectroscopic techniques, optical rotation and/or mass spectrometry data. The cytotoxic potential of eight of the aporphine alkaloids against four human cancer cell lines (Hep-2, MCF-7, B16-F10 and 786-0) was also evaluated.

Synthesis of Dihydrofuroaporphine Derivatives: Identification of a Potent and Selective Serotonin 5-HT1A Receptor Agonist

A series of new aporphine analogues were synthesized and pharmacologically evaluated. 11-Allyloxy-(17), 11-propargyloxy-(20), and dihydrofuro-(19) aporphines displayed the highest affinity at the 5-HT(1A) receptor with K(i) values of 12.0, 14.0, and 6.7 nM, respectively. The high binding potential of the diastereomeric mixture of aporphine 19 was found residing in the cis-diastereomer (cis-19). [(35)S]GTP gamma S function assays on 5-HT(1A) receptor indicated that aporphines 17 and 20 were partial agonists, while trans-19 behaved as a high efficacy full antagonist and cis-19 was a full agonist. The agonistic property of cis-19 at the 5-HT(1A) receptor was further confirmed in vitro and in vivo. This compound may be useful as a potential treatment for anxiety.

Aporphine Alkaloid Synthesis and Diversification via Direct Arylation

AbstractPalladium‐catalyzed direct arylation of aryl chlorides, bromides and iodides has been applied to the preparation of new aporphine analogues including C2‐substituted aporphines by reaction with benzodioxole, pyridine N‐oxide and pyrazine N‐oxide. Successful application of direct arylation in these diversification reactions highlights its utility not only in convergent, but also in divergent synthesis. We also describe enantioselective syntheses of (R)‐nornuciferine and (R)‐nuciferine employing a catalytic asymmetric transfer hydrogenation in high yield and excellent enantiomeric excess. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Central monoaminergic effects of two aporphine analogues to the putative serotonin-receptor agonist, 8-hydroxy-2-di- n-propylaminotetralin

Two aporphine analogues to the potent and selective serotonin (5-HT) agonist, 8-hydroxy-2-di- n-propylaminotetralin (8-OH-DPAT) were studied with regard to their actions upon central monoaminergic systems. The biochemical and behavioural findings indicate that 8-hydroxy- N-methyl-aporphine (8-OH-aporphine) and its N-n-propyl analogue (8-OH-PNA) possess weak dopamine/noradrenaline antagonist- and agonist-like properties, respectively. In addition, both aporphines seemed to only weakly influence serotoninergic transmission. The latter findings are compared to those of known serotonin agonists (e.g. 8-OH-DPAT), and are discussed with particular reference to the structural requirements for activation of central 5-HT receptors.

Chemical and pharmacological studies on derivatives of benzo[de]quinoline, II (author's transl)

Chemical and Pharmacological Studies on Derivatives of Benzo[de]quinoline, IISpirocompounds of type V (12–18) were synthesized by a carbenium ion cyclization reaction of the intermediates 7 and 11, respectively. 7 was prepared from 2‐oxocyclopentanepropionic acid via 1, 2, and 4–6; 11 from the same starting material via 1, 2, and 8–10. ‐ The spiro[7H‐benzo[de]quinolin‐7,1′‐cyclohexan]‐2′‐one 27 and other compounds of type VI could be synthesized from the (1‐isoquinolinyl)ethyl‐cyclohexanone 25: 25 is hydroxylated to the hydroxyketone 26; treatment of 26 with a mixture of sulfuric acid and oleum gives 27. The structure of 27 has been proved by transformation into the known spirocyclohexane 33. ‐ Aporphine analogues of type VII (38, 39) were synthesized from the cyclic ketone 34 via either the formylketone 35 and its methyl vinyl ketone adducts 36 and 37 or the methyl ethynyl ketone adduct 40. Compound 40 has also been cyclized to the 10‐hydroxy‐aporphine 42. 9 compounds of the types mentioned have been screened for hypotensive action in rats, and partly in cats and dogs. Only compound 13 · HCl proved to be (moderately) active in rats and dogs.

Aporphines 15 action of aporphine alkaloids on dopaminergic mechanisms in rat brain

Of eleven aporphine analogues tested on striatal adenylate cyclase only (−)-apomorphine and (±)-N-n-propyl-norapomorphine (±-(NPA)) were effective in stimulating the cyclase from rat brain. Inactive compounds included (±)-isoapomorphine, (−)-1,2-dihydroxyaporphine and (±)-10-hydroxy-N-n-propylnoraporphine. (+)-Bulbocapnine was an effective antagonist of the stimulating effects of dopamine or (−)-apomorphine on striatal adenylate cyclase. Injection of (−)-apomorphine into the lateral ventricle of rats with unilateral 6-hdyroxydopamine-induced lesions of the nigro-striatal pathway caused the animals to rotate away from the side of the lesion. Intraventricular injection of 25 μ (±)-10-hydroxy-N-n-propylnorapomorphine was ineffective in producing rotation. The results are discussed in relation to the structural requirements for CNS dopamine receptor agonists.