ABSTRACT
Ardisia crenata Sims (Myrsinaceae) occurs in two varieties differing in the fruit color, the red berries being common while the white ones are rare. The roots of red-berried A. crenata are a valued TCM product which contains bioactive benzoquinones such as embelin and rapanone. In this study we compared their profiles in different organs of the plant to provide an insight in the pattern of their accumulation within the two varieties. Moreover, cytotoxic activity against human melanoma and prostate cancer cells was evaluated. Quantitative HPLC revealed that the white-berried variety differs profoundly in the content of rapanone, with its total level of 606.5 mg/100 g d.w., as compared to 16.2 mg/100 g d.w. in A. crenata 'red'. Embelin was less distributed and found in minor amounts in both varieties. This is the first report on rapanone content in various parts of Ardisia crenata and on benzoquinones in the white-berried variety.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Ardisia/chemistry , Benzoquinones/pharmacology , Antineoplastic Agents, Phytogenic/analysis , Ardisia/physiology , Benzoquinones/analysis , Cell Line, Tumor , Chromatography, High Pressure Liquid , Fruit/chemistry , Humans , Male , Melanoma/drug therapy , Melanoma/pathology , Pigmentation , Plant Extracts/chemistry , Plant Extracts/pharmacology , Plant Roots/chemistry , Plants, Medicinal/chemistry , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathologyABSTRACT
Two triterpene saponins (IPS-1, IPS-2) for the first time were isolated from the roots of Impatiens parviflora DC. (Balsaminaceae). Their anti-inflammatory activity was evaluated by means of two in vitro models: anti-hyaluronidase and anti-denaturation assays. Both saponins were shown to be potent hyaluronidase inhibitors that affect the enzyme in a dose-dependent manner. The anti-hyaluronidase effect of IPS-2 (IC50 = 286.7 µg/mL) was higher than that of the reference drug: escin (IC50 = 303.93 µg/mL). Both saponins protected bovine serum albumin from heat-induced denaturation in a dose-dependent manner. IPS-1 demonstrated higher anti-denaturation effect (IC50 = 86.7 µg/ml) than IPS-2 (IC50 = 109.76 µg/mL) or the standard drug: acetylsalicylic acid (IC50 = 262.22 µg/mL). In conclusion, potent activity of IPS-1, IPS-2 in both in vitro assays shows that saponins from I. parviflora have anti-inflammatory activity. The obtained results allow to suggest that such compounds may be beneficial in inflammatory conditions, especially associated with excessive degradation of hyaluronic acid.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Impatiens/chemistry , Saponins/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Hyaluronoglucosaminidase/antagonists & inhibitors , Molecular Structure , Plant Roots/chemistry , Protein Denaturation/drug effects , Saponins/administration & dosage , Saponins/chemistry , Serum Albumin, Bovine/chemistry , Triterpenes/administration & dosage , Triterpenes/chemistry , Triterpenes/pharmacologyABSTRACT
The multireceptor strategy was implemented to obtain potential antipsychotics and/or antidepressants in a series of long-chain arylpiperazines bearing a tricyclic theophylline fragment. Their binding profile toward monoaminergic receptors (α1, 5-HT(1A), 5-HT(2A), 5-HT6, 5-HT7, D2, D3) was determined as well. The selected compounds 7 and 9 were tested in functional in vivo models and showed, like atypical antipsychotic drugs, presynaptic 5-HT(1A) receptor agonistic and postsynaptic 5-HT(1A), 5-HT(2A), and D2 receptor antagonistic activity.
Subject(s)
Antidepressive Agents, Tricyclic/chemical synthesis , Antidepressive Agents, Tricyclic/pharmacology , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/pharmacology , Theophylline/chemical synthesis , Theophylline/pharmacology , Animals , Antidepressive Agents, Tricyclic/metabolism , Antipsychotic Agents/metabolism , Behavior, Animal/drug effects , Body Temperature Regulation/drug effects , Dopamine D2 Receptor Antagonists/chemical synthesis , Dopamine D2 Receptor Antagonists/pharmacology , Male , Mice , Molecular Structure , Motor Activity/drug effects , Rats, Wistar , Receptors, Dopamine/drug effects , Receptors, Dopamine/metabolism , Receptors, Serotonin/drug effects , Receptors, Serotonin/metabolism , Serotonin 5-HT1 Receptor Agonists/chemical synthesis , Serotonin 5-HT1 Receptor Agonists/pharmacology , Serotonin 5-HT1 Receptor Antagonists/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists/pharmacology , Serotonin 5-HT2 Receptor Antagonists/chemical synthesis , Serotonin 5-HT2 Receptor Antagonists/pharmacology , Structure-Activity Relationship , Theophylline/analogs & derivatives , Theophylline/metabolismABSTRACT
BACKGROUND: Our previous studies in a group of arylpiperazine derivatives of 1,3-dimethyl-3,7-dihydro-purine-2,6-diones, aimed at chemical diversification of the purine-2,6-dione by introduction of hydrophobic substituent in a 7- or 8- position or elongation of the linker length between arylpiperazine and purine core, allowed a selection of potent 5-HT1A, 5-HT2A and 5-HT7 receptor ligands displaying anxiolytic and antidepressant properties. Continuing our research in this field, in the present studies we designed a new series of 8-aminoalkylamino (15-35) and 8-arylpiperazinylpropoxy (36-42) derivatives of 7-substituted 1,3-dimethyl-3,7-dihydropurine-2,6-dione as potential 5-HT1A, 5-HT2A and 5-HT7 receptor ligands with potential psychotropic activity. METHODS: Radioligand binding assays were employed for determining the affinity and the selectivity profile of the synthesized compounds for native 5-HT1A, 5-HT2A, and cloned 5-HT6 and 5-HT7 receptors. The functional activity of the selected compounds at 5-HT1A and 5-HT2A receptors was tested in the commonly used in vivo models. Antidepressant and anxiolytic properties were evaluated in the forced swim (FST) and the four-plate test (FPT) in mice, respectively. RESULTS: Among the evaluated series, selected 7-benzyl-8-((4-(4-(3-chlorophenyl)piperazin-1-yl)butyl)amino)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (21), a mixed 5-HT1A/5-HT2A/5-HT7 receptor ligand, produced an antidepressant-like effect in FST, and exerted anxiolytic-like activity in FPT. Another pharmacologically evaluated compound 42 (a mixed 5-HT1A/5-HT7 ligand) slightly, but non-significantly attenuated the immobility time of mice in FST and was devoid of activity in FPT. CONCLUSIONS: Study revealed advantage of mixed 5-HT1A/5-HT2A/5-HT7 receptor ligands over 5-HT1A/5-HT7 agents to display antidepressant- and anxiolytic-like activity. Modification of arylalkyl/allyl substituent in position 7 of purine-2,6-dione opens possibility for designing new 5-HT ligands with preserved p electron system and lower molecular weight.
Subject(s)
Anti-Anxiety Agents/pharmacology , Antidepressive Agents/pharmacology , Purines/pharmacology , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/chemistry , Antidepressive Agents/chemical synthesis , Antidepressive Agents/chemistry , Anxiety/drug therapy , Anxiety/physiopathology , Depression/drug therapy , Depression/physiopathology , Disease Models, Animal , Male , Mice , Purines/chemical synthesis , Purines/chemistry , Radioligand Assay , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT2A/metabolism , Receptors, Serotonin/metabolism , Structure-Activity RelationshipABSTRACT
A computer aided ligand design study of imidazolidine-2,4-dione derivatives was conducted in order to obtain compounds with dual 5-HT(1A) receptor and serotonin transporter (SERT) affinity. According to molecular modeling results, series of Mannich bases were chosen and synthesized. Investigated compounds were tested for 5-HT(1A) , 5-HT(2A) , α(1) and SERT affinity. Two selected compounds (5, 9) were characterized in functional experiments and possessed a pharmacological profile which may enhance SERT blocking efficacy - 5-HT(1A) partial agonism and 5-HT(2A) antagonism in one molecule. Furthermore these compounds displayed satisfactory selectivity over adrenergic α(1) receptors. The most promising compounds, 5-arylimidazolidine-2,4-dione derivatives with 4-(3-chlorophenyl)piperazinylmethyl moiety were tested for antidepressant and anxiolytic activity. In particular, compound 5 (5-(2-methoxyphenyl)-3-{1-[4-(3-chlorophenyl)piperazin-1-yl]methyl}-imidazolidine-2,4-dione), tested in the forced swim test in mice, exhibited a favorable antidepressant-like profile without affecting spontaneous locomotor activity.
Subject(s)
Anti-Anxiety Agents , Antidepressive Agents , Hydantoins , Mannich Bases , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Antidepressive Agents/chemical synthesis , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Binding Sites , Computer-Aided Design , Cricetinae , Dose-Response Relationship, Drug , Drug Design , Humans , Hydantoins/chemical synthesis , Hydantoins/chemistry , Hydantoins/pharmacology , Ligands , Male , Mannich Bases/chemical synthesis , Mannich Bases/chemistry , Mannich Bases/pharmacology , Mice , Molecular Docking Simulation , Molecular Structure , Motor Activity/drug effects , Protein Binding , Rats , Receptor, Serotonin, 5-HT2A/metabolism , SwimmingABSTRACT
A series of new quinoline- and isoquinoline-sulfonamide analogs of aripiprazole was synthesized to explore the influence of two structural features - replacement of ether/amide moiety with sulfonamide one, and localization of a sulfonamide group in the azine moiety. In contrast to aripiprazole, compound 33 (N-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)quinoline-7-sulfonamide) and 39 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)isoquinoline-3-sulfonamide) displaying multireceptor 5-HT(1A)/5-HT(2A)/5-HT(7)/D(2)/D(3) profile, and behaving as 5-HT(1A) agonists, D(2) partial agonists, and 5-HT(2A)/5-HT(7) antagonists, produced significant antidepressant activity in FST in mice. On the other hand, their 4-isoquinolinyl analog 40 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)isoquinoline-4-sulfonamide), with similar receptor binding and functional profile, additionally displayed remarkable antipsychotic properties in the MK-801-induced hyperlocomotor activity in mice.
Subject(s)
Antidepressive Agents/pharmacology , Antipsychotic Agents/pharmacology , Dopamine D2 Receptor Antagonists , Piperazines/chemistry , Piperazines/pharmacology , Quinolones/chemistry , Quinolones/pharmacology , Receptors, Dopamine D3/antagonists & inhibitors , Receptors, Serotonin/metabolism , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/chemistry , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/chemistry , Aripiprazole , Behavior, Animal/drug effects , Dizocilpine Maleate/pharmacology , Dose-Response Relationship, Drug , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Isoquinolines/pharmacology , Mice , Molecular Structure , Motor Activity/drug effects , Piperazines/chemical synthesis , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolines/pharmacology , Quinolones/chemical synthesis , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
Two series of arylpiperazinyl-alkyl quinoline-, isoquinoline-, naphthalene-sulfonamides with flexible (13-26) and semi-rigid (33-36) alkylene spacer were synthesized and evaluated for 5-HT(1A), 5-HT(2A), 5-HT(6), 5-HT(7) and selected compounds for D(2), D(3), D(4) receptors. The compounds with a mixed 5-HT and D receptors profile 16 (N-{4-[4-(3-chlorophenyl)-piperazin-1-yl]-butyl}-3-quinolinesulfonamide) and 36 (4-(4-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethyl}-piperidine-1-sulfonyl)-isoquinoline), displaying antagonistic activity at 5-HT(7), 5-HT(2A), D(2) postsynaptic sites, produced antidepressant-like effects in the forced swim test in mice and showed significant anxiolytic activity in the plus-maze test in rats. The lead compound 36, a multi-receptor 5-HT(2A)/5-HT(7)/D(2)/D(3)/D(4) agent, also displayed significant antipsychotic properties in the MK-801-induced hyperlocomotor activity in mice.
Subject(s)
Central Nervous System/drug effects , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Animals , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacology , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Isoquinolines/pharmacology , Mice , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacology , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolines/pharmacology , Rats , Receptor, Serotonin, 5-HT1A , Receptor, Serotonin, 5-HT2A , Receptors, Serotonin/metabolism , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
Novel arene- and quinolinesulfonamides were synthesized using different solutions and a solid-support methodology, and were evaluated for their affinity for 5-HT(1A), 5-HT(2A), 5-HT(6), and 5-HT(7) receptors. Compound 54 (N-Ethyl-N-[4-(1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-2-yl)butyl]-8-quinolinesulfonamide) was identified as potent 5-HT(7) antagonist (K(i)=13 nM, K(B)=140 nM) with good selectivity over 5-HT(1A), 5-HT(2A), 5-HT(6) receptors. In the FST in mice, it reduced immobility in a manner similar to the selective 5-HT(7) antagonist SB-269970.
