RESUMO
Acetylcholinesterase (AChE) inhibitory activity is one of the proposed targets for indole analogs. Simple indoles with substitution of methoxy, carboxy or hydroxy at the benzene ring showed a low percent of inhibitory activity in eel-AChE. Adding a side chain at the pyrrole ring, such as serotonin, ß-carbolines and quinolines (the bioisostere of indole), improved the inhibitory activity significantly. However, proper substitution and conformation of the ring were required for good binding. The result of inhibition in human-AChE of serotonin, ß-carbolines and quinolines showed similar profile as eel-AChE with lower magnitude. The data from molecular docking showed that they shared the same binding site as galantamine.
Assuntos
Acetilcolinesterase , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Indóis/síntese química , Acetilcolinesterase/metabolismo , Sítios de Ligação , Carbolinas/química , Carbolinas/farmacologia , Inibidores da Colinesterase/química , Ativação Enzimática/efeitos dos fármacos , Humanos , Indóis/química , Indóis/farmacologia , Conformação Molecular , Quinolinas/química , Quinolinas/farmacologiaRESUMO
This study investigated the effect of Eulophia macrobulbon (EM) extract on sexual performance in aged-related erectile dysfunction (ED) rats. The ethanol EM extract at the doses of 15, 150, and 450 and sildenafil citrate at the dose of 5 mg/kg body weight (BW) were administered orally to the aged male rats once daily for 21 days. Mating parameters and intracavernosal pressure (ICP) were measured to evaluate their sexual and erection functions. Numbers of sperm and sperm motility as well as the diameter of seminiferous tubules were observed. The serum testosterone and 3',5'-cyclic guanosine monophosphate (cGMP) concentration in the rat penile tissue were analyzed. The results showed the significant increased sexual motivation, copulatory performance, and ICP of aged rats treated with sildenafil citrate and all doses of EM extract as compared to control aged rats. Moreover, their serum testosterone levels were slightly increased and significant increase in penile cGMP concentration was observed in these aged rats treated with sildenafil citrate and EM extract. The results suggest that treatment with EM could inhibit activity of PDE5 in penile tissue resulting in the increased cGMP level and bring to the improvement of erectile function and sexual performance.
Assuntos
Afrodisíacos/farmacologia , Disfunção Erétil/tratamento farmacológico , Orchidaceae/química , Extratos Vegetais/farmacologia , Animais , Masculino , Ereção Peniana , Piperazinas , Purinas , Ratos , Citrato de Sildenafila/farmacologia , Motilidade dos Espermatozoides , SulfonasRESUMO
Phosphodiesterase 5 (PDE5) inhibitors can be used for the treatment of erectile dysfunction and pulmonary hypertension. In order to search for new leads of PDE5 inhibitors, we investigated the chemical constituents of the tubers of Eulophia macrobulbon (E.C. Parish & Rchb. f.) Hook. f. A new phenanthrene, 9,10-dihydro-4-(4'-hydroxybenzyl)-2,5-dimethoxyphenanthrene-1,7-dio (1) and three known phenanthrenes i.e., 1-(4'-hydroxybenzyl)-4,8- dimethoxyphenanthrene-2,7-diol (2), (9,10-dihydro-2,5-dimethoxyphenanthrene-1,7-diol (3) and 1,5,7-trimethoxyphenanthrene-2,6-diol). (4) were isolated Among these, 2 was the most potent PDE5 inhibitor (IC50 =1.67±0.54 µM) evaluated by the [3H]cGMP radioassay method, whereas 1 showed mild activity (IC50 = 62.3±3.3 µM). Their inhibitory selectivities against PDE5 over PDE6 were also studied. This study suggests phenanthrenes as a new class of PDE5 inhibitors.
Assuntos
Orchidaceae/química , Fenantrenos/química , Fenantrenos/farmacologia , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/farmacologia , Animais , GMP Cíclico/metabolismo , Disfunção Erétil/tratamento farmacológico , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Masculino , Estrutura Molecular , Extratos Vegetais/química , Raízes de Plantas/química , Ratos , Especificidade por SubstratoRESUMO
Twenty bromotyrosine alkaloids, including a new compound, 13-oxosubereamolline D (5), were isolated from the Thai sponge Acanthodendrilla sp. Their structures were determined by analyses of 1D- and 2D-NMR, high-resolution mass, and circular dichroism data. The complete 1H and 13C NMR assignments of 5,7ß-dichlorocavernicolin (19) and 5,7α-dichlorocavernicolin (20) are described herein for the first time. The acetylcholinesterase (AChE) inhibitory activity of all isolated compounds was evaluated. Only homoaerothionin (7) and fistularin 1 (10) exhibited inhibitory activity against human recombinant AChE (hrAChE) with IC50s of 4.5 and 47.5 µM, respectively. The hrAChE inhibition kinetics of 7, the most potent alkaloid, showed increased Km and unchanged Vmaxvalues, suggesting its competitive mode of inhibition. The spirocyclohexadienylisoxazole and the length of the alkyl diamine linkage were proposed as the crucial parts for its strong inhibitory activity. This finding indicates a therapeutic potential for 7 in acetylcholine-related diseases, most importantly Alzheimer's disease.
Assuntos
Alcaloides/química , Inibidores da Colinesterase/química , Poríferos/química , Tirosina/análogos & derivados , Acetilcolinesterase/análise , Animais , Humanos , Cinética , Estrutura Molecular , Tailândia , Tirosina/químicaRESUMO
OBJECTIVES: Phosphodiesterase (PDE)-5 inhibitors are useful as vasodilators for the treatment of pulmonary arterial hypertension. We aimed to study curcumin analogues for PDE5 inhibitory activity and vasorelaxation of rat pulmonary arteries. METHODS: Three natural curcuminoids (1-3) and six synthetic analogues (4-9) were tested for PDE5 and PDE6 inhibitory activities using enzymatic radioassay. Their vasorelaxation was measured using freshly isolated segments of rat pulmonary artery and aorta. KEY FINDINGS: Curcuminoids (1-3) mildly inhibited PDE5 (half maximal inhibitory concentration (IC50 ) = 18 µm): the metamethoxyl of curcumin was important for PDE5 inhibition. But hydroxyl rearrangements, removing both methoxyls and one ketomethylene, yielded the potent 7 and 9 (IC50 = 4 µm) (compared with sildenafil, IC50 = 0.03 µm). Only 1, 3 and 4 were PDE5 selective over PDE6. Triazole-carboxylic addition provided water-solubility while preserving potency. All analogues possessed concentration-dependent vasorelaxant activity on pulmonary arteries (40% of maximal effective concentration (EC40 ) = 29-90 µm, maximum response = 60-90% at 300 µm), while compounds (1-8) were weakly acting in aorta (maximum response <40%). Only demethoxycurcumin (2) and analogues 5, 8, 9 had endothelium-dependent actions. Sildenafil was highly potent (EC40 = 0.04 µm) and highly endothelium dependent in pulmonary artery but weak on intact aorta (EC40 = 1.8 µm). Activity profiles suggest actions through additional cell pathways for promoting vasorelaxation. CONCLUSIONS: Curcumin analogues are potential leads for developing efficacious and selective PDE5 inhibitors and other pathologies of pulmonary hypertension.
Assuntos
Curcumina/análogos & derivados , Inibidores da Fosfodiesterase 5/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Relação Dose-Resposta a Droga , Endotélio Vascular/metabolismo , Inibidores da Fosfodiesterase 5/química , Ratos , Relação Estrutura-Atividade , Vasodilatação/efeitos dos fármacosRESUMO
Fifteen bromotyrosine-derived alkaloids were isolated from the sponge Pseudoceratina cf. purpurea. The acetylcholinesterase-inhibiting activity of all the isolated compounds were examined; to purealidin Q, isoanomoian A, aplyzanzine A, and aplysamine 2 were active with IC50 values of 1.2, 70, 104, and 1.3 µM, respectively. On the other hand, antiproliferative activity against MCF-7 cells of aerophobin 1 gave an IC50 value of 0.8 µM. The Michaelis-Menten plots of the active alkaloids indicated that all the four compounds inhibited acetylcholinesterase in a non-competitive manner. The structures of the active compounds suggested that the N,N-dimethylaminopropyloxydibromotyramine moiety may play an important role in the enzyme-inhibiting activity, presumably on the anionic and hydrophobic binding sites.
Assuntos
Acetilcolinesterase/metabolismo , Alcaloides/química , Alcaloides/farmacologia , Inibidores da Colinesterase/química , Tirosina/análogos & derivados , Proliferação de Células/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Ativação Enzimática/efeitos dos fármacos , Humanos , Células MCF-7 , Estrutura Molecular , Tirosina/química , Tirosina/farmacologiaRESUMO
The ethanolic extract from stems of a Thai medicinal plant, Alstonia macrophylla Wall. ex G. Don (Apocynaceae) showed a significant inhibitory effect on acetylcholinesterase (AChE) determined by using Ellman assay. Four compounds i.e., a bisindole alkaloid, macralstonine (1), a new bisindole alkaloid, thungfaine (2), a secoiridoid glycoside, sweroside (3) and a new secoiridoid glycoside, naresuanoside (4) were isolated. Compound 4 showed moderate AChE and butyrylcholinesterase (BChE) inhibitory effects. Interestingly, compound 4 inhibited cell growth on human androgen-sensitive prostate cancer cell line (LNCaP) but no effect on viability of human foreskin fibroblast cells (HF).