Partial Agonist Activity Research Articles

ID:15929 Secondary Respiratory Outcomes of a Phase 1 Placebo-Controlled Trial: Buprenorphine Buccal Film Versus Oral Oxycodone

Buprenorphine is a Schedule III opioid with partial mu-opioid receptor agonist activity.1 The unique receptor activity profile of buprenorphine induces effective analgesia and decreases the risk of respiratory depression when compared with Schedule II full-mu opioid receptor agonists.1,2 This phase 1 study (ClinicalTrials.gov, NCT03996694) was conducted to directly compare the effect of buprenorphine buccal film (BioDelivery Sciences International, Inc.) with that of a full mu-opioid receptor agonist, oxycodone hydrochloride (immediate-release), on respiratory drive.3 The primary outcome of this study was the maximum decrease in minute ventilation; buprenorphine buccal film did not suppress respiratory drive compared with placebo, whereas oxycodone showed a significant dose-dependent decrease in respiratory drive. Additional clinically relevant outcomes were assessed throughout the study and are presented here.

Aripiprazol and Hypersexuality: when partial is to much

IntroductionA growing number of published cases has showed that hypersexual behavior may arise with treatment with second-generation antipsychotics, including aripiprazole and olanzapine. Aripiprazole is a second-generation antipsychotic commonly used to treat schizophrenia and bipolar disorder. It has a unique pharmacologic profile acting as a partial agonist of the dopamine D2 receptor, as a partial agonist at the 5-HT1A receptor, and as an antagonist at the 5-HT2A receptor. Literature shows that medication with partial dopaminergic agonistic activity can cause compulsive behaviors, such as pathological gambling, compulsive eating, compulsive shopping, and hypersexuality. Although it is difficult to predict who would develop these behaviors, the literature suggests that patients at a higher risk of developing impulsive behaviors include those with a personal or family history of obsessive-compulsive disorder, impulse control disorder, bipolar disorder, impulsive personality, alcoholism, drug abuse, or other addictive behaviors.ObjectivesHere, we present a case of a 32-year-old male who developed hypersexuality symptoms after receiving aripiprazole as treatment for bipolar disorder.MethodsWe have done a literature review using the MeSH terms Aripiprazole and hypersexuality in the “PubMed”.ResultsAfter switching Aripiprazole to Risperidone the hypersexuality symptoms started to decrease and got almost complete relief after 2 weeks.ConclusionsThis case highlights the rare hypersexuality side effect that can arise in patients receiving aripiprazole for bipolar disorder treatment. Clinicians should be aware of the increased risk of hypersexuality and other impulsive behaviors as they can significantly impair a patient’s daily functioning.DisclosureNo significant relationships.

Buprenorphine and Cardiac Surgery: Navigating the Challenges of Pain Management

OVER THE LAST 2 decades, buprenorphine has been used for the treatment of pain, opioid addiction, and detoxification. It has unique properties, including partial agonist activity at the mu receptor, while also exhibiting antagonism at the kappa receptor. 1 Goel A Azargive S Lamba W et al. The perioperative patient on buprenorphine: A systematic review of perioperative management strategies and patient outcomes. Can J Anaesth. 2019; 66: 201-217 Crossref PubMed Scopus (32) Google Scholar The half-life is highly variable with each patient, but it may extend up to 60 hours. In addition, even low doses will outcompete other opioids to bind receptors, rendering other opioids ineffective unless very high doses are used. 2 Anderson TA Quaye ANA Ward EN et al. To stop or not, that is the question: Acute pain management for the patient on chronic buprenorphine. Anesthesiology. 2017; 126: 1180-1186 Crossref PubMed Scopus (83) Google Scholar Although this may be advantageous in the outpatient setting, the pharmacokinetic and pharmacodynamic properties of buprenorphine can complicate the perioperative management of pain when these patients present for surgery. Herein, the authors present a case during which a patient who was started on buprenorphine for addiction therapy was referred subsequently for cardiac surgery during the same inpatient hospital admission.

Structure‐Function Relationship of the 20‐HETE‐GPR75 pairing: Development and characterization of agonist, partial agonists, and receptor blockers

20‐Hydroxyeicosatetraenoic acid (20‐HETE) and its receptor (20HR), GPR75 (Gq), exhibit diverse bioactions that promote the activation of pro‐hypertensive, ‐diabetic and ‐obesity signals. The pharmacological properties associated with analogues that target GPR75 remain unclear. The screening of 20‐HETE and synthetic 20‐HETE analogues using changes of intracellular calcium (iCa2+) in the endothelial cell line, EA.hy926, as a measure of 20HR activation, revealed that the compounds 20‐HETE (10 nM), sodium 20‐hydroxyeicosa‐5Z,14Z‐dienoate (20‐5,14‐HEDE) (10 nM) and sodium 14‐((6‐hydroxyhexyl)oxy)tetradec‐5(Z)‐enoate (5Z‐HOTE) (10 nM) promote significant and comparable elevations in iCa2+. In EA.hy926 cells, 20‐HETE elicited a half‐maximal effective concentrations (EC50) with respect to iCa2+ of 1.228 e‐9 M while 20‐5,14‐HEDE’s EC50 was 6.908 e‐10 M. The water‐soluble derivative of 20‐5,14‐HEDE, SOLAGO, exhibited a marked and leftward shift in the dose‐response with an EC50 of 2.702 e‐10 M. Interestingly, sodium 19(R)‐ and 19(S)‐hydroxyeicosa‐5(Z),14(Z)‐dienoate, analogues of 19(R)‐HETE, an endogenous 20HR blocker (20HRB), demonstrated partial agonist activity; elevating iCa2+to 1.6‐ and 2‐fold over baseline vehicle treatment, respectively. With respect to 20HR blockers, the water‐soluble 20HRBs 2,5,8,11,14,17‐hexaoxanonadecan‐19‐yl 20‐hydroxyeicosa‐6(Z),15(Z)‐dienoate (20‐SOLA) and N‐disodium succinate‐20‐hydroxyeicosa‐6(Z),15(Z)‐diencarboxamide (AAA) displayed potent half‐maximal inhibitory concentrations (IC50s) of 8.059 e‐10 and 5.356 e‐10 M, respectively. The 19(R)‐HETE analogue sodium (19(R)‐hydroxyeicosa‐5(Z),14(Z)‐dienoyl)glycinate (19(R)‐HEDGE) also demonstrated a strong yet less potent IC50 response of 6.715 e‐9 M. Further studies are necessary to better understand the structure‐function relationships between 20HR agonists, partial agonists, and receptor blockers. These data would allow for the development of novel 20HRBs for the treatment of various pathologies associated with elevations in 20‐HETE including hypertension, cancer, diabetes, and obesity.

Polimorfisme Gen DRD2 rs1799732 (-141c) Terhadap Terapi Aripiprazole pada Pasien Skizofrenia

The polymorphism rs1799732 (-141C) is located in the 5 'promoter region of DRD2, where these SNPs can influence modulation of transcription activity and D2 receptor density. This study aims to provide a literature review of the polymorphism rs1799732 (-141C) because this gene polymorphism is the most common gene polymorphism in the world related to schizophrenia. This gene polymorphism is known to play a role in the variability of response to aripiprazole antipsychotic therapy in schizophrenic patients. The type of review used in this article is in the form of a literature review of 38 literature from various journals and textbooks. Schizophrenia is a disease that can affect the brain. In the brain there is a chemical delivery of messages that will forward messages around the brain. In schizophrenic patients, dopamine is excessive, while dopamine levels play an important role in feelings of pleasure and experiences of different moods. If dopamine levels are imbalanced, sufferers can experience both positive and negative symptoms. The hypothesis states that excessive dopaminergic activity can lead to schizophrenia. The dopaminergic system plays an important role as a modulator of affective and cognitive functions. Dopamine D2 receptor polymorphism is known to be a risk factor for schizophrenia. Polymorphisms are determinants of clinical symptoms and can play a role in the effectiveness and side effects of antipsychotics, including aripiprazole. Aripiprazole is a second-generation antipsychotic, an antipsychotic with partial agonist activity against dopamine D2.

Novel Sunifiram-carbamate hybrids as potential dual acetylcholinesterase inhibitor and NMDAR co-agonist: simulation-guided analogue design and pharmacological screening

An efficient method for synthesising NMDAR co-agonist Sunifiram (DM235), in addition to Sunifram-carbamate and anthranilamide hybrids, has been developed in high yields via protecting group-free stepwise unsymmetric diacylation of piperazine using N-acylbenzotiazole. Compounds 3f, 3d, and 3i exhibited promising nootropic activity by enhancing acetylecholine (ACh) release in A549 cell line. Moreover, the carbamate hybrid 3f was found to exhibit higher in vitro potency than donepezil with IC50 = 18 ± 0.2 nM, 29.9 ± 0.15 nM for 3f and donepezil, respectively. 3f was also found to effectively inhibit AChE activity in rat brain (AChE = 1.266 ng/mL) compared to tacrine (AChE = 1.137 ng/ml). An assessment of the ADMET properties revealed that compounds 3f, 3d, and 3i are drug-like and can penetrate blood–brain barrier. Findings presented here showcase highly potential cholinergic agents, with expected partial agonist activity towards glycine binding pocket of NMDAR which could lead to development and optimisation of novel nootropic drugs.

4-Heteroaryl Substituted Amino-3,5-Dicyanopyridines as New Adenosine Receptor Ligands: Novel Insights on Structure-Activity Relationships and Perspectives

A new set of amino-3,5-dicyanopyridines was synthesized and biologically evaluated at the adenosine receptors (ARs). This chemical class is particularly versatile, as small structural modifications can influence not only affinity and selectivity, but also the pharmacological profile. Thus, in order to deepen the structure–activity relationships (SARs) of this series, different substituents were evaluated at the diverse positions on the dicyanopyridine scaffold. In general, the herein reported compounds show nanomolar binding affinity and interact better with both the human (h) A1 and A2A ARs than with the other subtypes. Docking studies at hAR structure were performed to rationalize the observed affinity data. Of interest are compounds 1 and 5, which can be considered as pan ligands as binding all the ARs with comparable nanomolar binding affinity (A1AR: 1, Ki = 9.63 nM; 5, Ki = 2.50 nM; A2AAR: 1, Ki = 21 nM; 5, Ki = 24 nM; A3AR: 1, Ki = 52 nM; 5, Ki = 25 nM; A2BAR: 1, EC50 = 1.4 nM; 5, EC50 = 1.12 nM). Moreover, these compounds showed a partial agonist profile at all the ARs. This combined AR partial agonist activity could lead us to hypothesize a potential effect in the repair process of damaged tissue that would be beneficial in both wound healing and remodeling.

PPL-138 (BU10038): A bifunctional NOP/mu partial agonist that reduces cocaine self-administration in rats

The search for new and effective treatments for cocaine use disorder (CUD) is a priority. We determined whether PPL-138 (BU10038), a compound with partial agonist activity at both nociceptin opioid peptide (NOP) and mu-opioid receptors, reduces cocaine consumption, reinstatement, and whether the compound itself produces reinforcing effects in rats. Using an intermittent access (IntA) cocaine self-administration procedure, we found that PPL-138 (0.1 and 0.3 mg/kg) effectively decreased the total number of cocaine infusions and burst-like cocaine intake in both male and female rats. Responses for food in an IntA model of food self-administration were not altered for either sex, although locomotor activity was increased in female but not male rats. Blockade of NOP receptors with the selective antagonist J-113397 (5 mg/kg) did not prevent the PPL-138-induced suppression of cocaine self-administration, whereas blockade of mu-opioid receptors by naltrexone (1 mg/kg) reversed such effect. Consistently, treatment with morphine (1, 3, and 10 mg/kg) dose-dependently reduced IntA cocaine self-administration measures. PPL-138 also reduced reinstatement of cocaine seeking at all doses examined. Although an initial treatment with PPL-138 (2.5, 10, and 40 μg/kg/infusion) appeared rewarding, the compound did not maintain self-administration behavior. Animals treated with PPL-138 showed initial suppression of cocaine self-administration, which was eliminated following repeated daily dosing. However, suppression of cocaine self-administration was retained when subsequent PPL-138 treatments were administered 48 h apart. These findings demonstrate that the approach of combining partial NOP/mu-opioid activation successfully reduces cocaine use, but properties of PPL-138 seem to depend on the timing of drug administration.

Pyrrolidinyl benzofurans and benzodioxanes: Selective α4β2 nicotinic acetylcholine receptor ligands with different activity profiles at the two receptor stoichiometries

A series of racemic benzofurans bearing N-methyl-2-pyrrolidinyl residue at C(2) or C(3) has been synthesized and tested for affinity at the α4β2 and α3β4 nicotine acetylcholine receptors (nAChRs). As previously reported for the benzodioxane based analogues, hydroxylation at proper position of benzene ring results in high α4β2 nAChR affinity and α4β2 vs. α3β4 nAChR selectivity. 7-Hydroxy-N-methyl-2-pyrrolidinyl-1,4-benzodioxane (2) and its 7- and 5-amino benzodioxane analogues 3 and 4, which are all α4β2 nAChR partial agonists, and 2-(N-methyl-2-pyrrolidinyl)-6-hydroxybenzofuran (12) were selected for functional characterization at the two α4β2 stoichiometries, the high sensitivity (α4)2(β2)3 and the low sensitivity (α4)3(β2)2. The benzene pattern substitution, which had previously been found to control α4β2 partial agonist activity and α4β2 vs. α3β4 selectivity, proved to be also involved in stoichiometry-selectivity. The 7-hydroxybenzodioxane derivative 2 selectively activates (α4)2(β2)3 nAChR, which cannot be activated by its 5-amino analogue 4. A marginal structural modification, not altering the base pyrrolidinyl benzodioxane scaffold, resulted in opposite activity profiles at the two α4β2 nAChR isoforms providing an interesting novel case study.

Carboxamide Derivatives Are Potential Therapeutic AHR Ligands for Restoring IL-4 Mediated Repression of Epidermal Differentiation Proteins.

Atopic dermatitis (AD) is a common T-helper 2 (Th2) lymphocyte-mediated chronic inflammatory skin disease characterized by disturbed epidermal differentiation (e.g., filaggrin (FLG) expression) and diminished skin barrier function. Therapeutics targeting the aryl hydrocarbon receptor (AHR), such as coal tar and tapinarof, are effective in AD, yet new receptor ligands with improved potency or bioavailability are in demand to expand the AHR-targeting therapeutic arsenal. We found that carboxamide derivatives from laquinimod, tasquinimod, and roquinimex can activate AHR signaling at low nanomolar concentrations. Tasquinimod derivative (IMA-06504) and its prodrug (IMA-07101) provided full agonist activity and were most effective to induce FLG and other epidermal differentiation proteins, and counteracted IL-4 mediated repression of terminal differentiation. Partial agonist activity by other derivatives was less efficacious. The previously reported beneficial safety profile of these novel small molecules, and the herein reported therapeutic potential of specific carboxamide derivatives, provides a solid rationale for further preclinical assertation.

Phenolic Lipids Derived from Cashew Nut Shell Liquid to Treat Metabolic Diseases.

Metabolic diseases are increasing at staggering rates globally. The peroxisome proliferator-activated receptors (PPARα/γ/δ) are fatty acid sensors that help mitigate imbalances between energy uptake and utilization. Herein, we report compounds derived from phenolic lipids present in cashew nut shell liquid (CNSL), an abundant waste byproduct, in an effort to create effective, accessible, and sustainable drugs. Derivatives of anacardic acid and cardanol were tested for PPAR activity in HEK293 cell co-transfection assays, primary hepatocytes, and 3T3-L1 adipocytes. In vivo studies using PPAR-expressing zebrafish embryos identified CNSL derivatives with varying tissue-specific activities. LDT409 (23) is an analogue of cardanol with partial agonist activity for PPARα and PPARγ. Pharmacokinetic profiling showed that 23 is orally bioavailable with a half-life of 4 h in mice. CNSL derivatives represent a sustainable source of selective PPAR modulators with balanced intermediate affinities (EC50 ∼ 100 nM to 10 μM) that provide distinct and favorable gene activation profiles for the treatment of diabetes and obesity.

Split-thickness Skin Grafting in the Management of Cutaneous Sequelae of Intramuscular Pentazocine Injections: A Novel Approach

Pentazocine, a synthetic opioid with partial agonist and antagonist activity administered by parenteral injection, was used clinically in the 1970s. Dermatologic complications at injection sites were reported soon after its introduction. These complications are thought to be underreported. Many well-documented cases describe the development of fibrosis and calcinosis at the site of parenteral pentazocine injections, but few reports document management or successful treatment of the long-term sequelae of these manifestations. The successful use of STSG for the treatment of chronic nonhealing ulcers secondary to pentazocine-induced cutaneous fibrosis in a 78-year-old male is presented. In the early 1970s, he was started on 3-times-daily intramuscular pentazocine injections to treat pain secondary to ulcerative colitis. He injected himself in the proximal thighs and buttocks for a period of approximately 10 years. He gradually developed severe soft tissue calcifications of both buttocks and anterior thighs. In the mid-to-late 1980s, the pentazocine injections were discontinued. The diffuse sclerosis and disfiguring fibrosis remained. This case underscores the lasting effects of pentazocine-induced cutaneous sclerosis and fibrosis, with cutaneous complications manifesting in this patient even decades after use. It also highlights the novel use of STSG as a treatment strategy for these cutaneous complications.

Abstract- Poster

Introduction:Tapentadol is a centrally acting synthetic opioid analgesic which has partial opioid agonist and norepinephrine reuptake inhibitor action with a relatively higher μ-affinity. It has abuse potential, and classified as scheduled drug, yet currently it is not known to be an opioid which is widely misused in India.Case report:A 22yr old male was introduced to Tablet tapentadol by his friends. Initially he started taking 2-3 tablets(50mg) per day orally. Later he was suggested by his friend to try intravenous route and as it was more pleasurable he continued to use the drug intravenously. His opioid use gradually increased from 5 tablets per day to a maximum of 10 tablets per day(max dose upto 600mg) with craving, tolerance, withdrawal symptoms, loss of control within the initial 1-2yrs.He also occasionally used heroin whenever he got access to it. History of occasional use of alcohol, tobacco and cannabis was present. He presented to OPD with withdrawal symptoms and a blister in the left forearm which within few days became an abscess and he was referred to a surgeon and was diagnosed as Necrotizing fasciitis, which was surgically corrected and split skin grafting was done. He was later started on opioid substitution therapy with tablet buprenorphine and is currently maintaining abstinence.

The effect of buprenorphine vs. methadone on opioid-mediated responses in human placental explants

Buprenorphine treatment for maternal opioid use disorder (OUD) is associated with less severe neonatal withdrawal compared to methadone, but little is known about the effects of a partial opioid agonist on the placenta. Opioids are known to stimulate in vitro secretion of basal human chorionic gonadotropin (hCG) and acetylcholine (ACh), but chronic exposure has been shown to downregulate these responses. Given its partial agonist activity, we hypothesized that buprenorphine would be associated with less downregulation, and therefore more robust opioid-mediated responses as compared to methadone, a full agonist.

Partial Agonistic Actions of Sex Hormone Steroids on TRPM3 Function.

Sex hormone steroidal drugs were reported to have modulating actions on the ion channel TRPM3. Pregnenolone sulphate (PS) presents the most potent known endogenous chemical agonist of TRPM3 and affects several gating modes of the channel. These includes a synergistic action of PS and high temperatures on channel opening and the PS-induced opening of a noncanonical pore in the presence of other TRPM3 modulators. Moreover, human TRPM3 variants associated with neurodevelopmental disease exhibit an increased sensitivity for PS. However, other steroidal sex hormones were reported to influence TRPM3 functions with activating or inhibiting capacity. Here, we aimed to answer how DHEAS, estradiol, progesterone and testosterone act on the various modes of TRPM3 function in the wild-type channel and two-channel variants associated with human disease. By means of calcium imaging and whole-cell patch clamp experiments, we revealed that all four drugs are weak TRPM3 agonists that share a common steroidal interaction site. Furthermore, they exhibit increased activity on TRPM3 at physiological temperatures and in channels that carry disease-associated mutations. Finally, all steroids are able to open the noncanonical pore in wild-type and DHEAS also in mutant TRPM3. Collectively, our data provide new valuable insights in TRPM3 gating, structure-function relationships and ligand sensitivity.

Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties.

Partial agonist activity at the dopamine D2 receptor (DRD2) is a key feature of third-generation antipsychotics (TGAs). However, TGAs also act as antagonists or weak partial agonists to the serotonin (5-hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR). Here we present the crystal structures of aripiprazole- and cariprazine-bound human 5-HT2AR. Both TGAs adopt an unexpected 'upside-down' pose in the 5-HT2AR binding pocket, with secondary pharmacophores inserted in a similar way to a 'bolt'. This insight into the binding modes of TGAs offered a structural mechanism underlying their varied partial efficacies at 5-HT2AR and DRD2. These structures enabled the design of a partial agonist at DRD2/3 and 5-HT1AR with negligible 5-HT2AR binding that displayed potent antipsychotic-like activity without motor side effects in mice. This TGA lead also had antidepressant-like effects and improved cognitive performance in mouse models via 5-HT1AR. This work indicates that 5-HT2AR affinity is a dispensable contributor to the therapeutic actions of TGAs.

2-Phenylcyclopropylmethylamine Derivatives as Dopamine D2 Receptor Partial Agonists: Design, Synthesis, and Biological Evaluation.

Partial agonist activity at the dopamine D2 receptor (D2R) is the primary pharmacological feature of the third-generation antipsychotics─aripiprazole, brexpiprazole, and cariprazine. However, all these drugs share a common phenyl-piperazine moiety as the primary pharmacophore. In this study, we designed and synthesized a series of novel compounds based on the 2-phenylcyclopropylmethylamine (PCPMA) scaffold and studied their pharmacological activity at the D2R. A number of potent D2R partial agonists were identified through binding affinity screening and functional activity profiling in both G protein and β-arrestin assays. The structure-functional activity relationship results showed that the spacer group is crucial for fine-tuning the intrinsic activity of these compounds. Compounds (+)-14j and (+)-14l showed good pharmacokinetic properties and an unexpected selectivity against the serotonin 2A (5-HT2A) receptor. Preliminary suppressive effects in a mouse hyperlocomotion model proved that these PCPMA-derived D2R partial agonists are effective as potential novel antipsychotics.

Paradoxical Increase in Body Mass Induced by Beta-Guanidinopropionic Acid in Juvenile Spontaneously Hypertensive Rats.

BackgroundThe adenosine triphosphate (ATP) regenerating enzyme creatine kinase (CK) is intimately involved in blood pressure generation. Consequently, the creatine transporter and CK inhibitor beta-guanidinopropionic acid (GPA) successfully reduced blood pressure in 16-week-old spontaneously hypertensive rats (SHR), but GPA may cause growth retardation in juvenile mammals. This report considers a serendipity observation of paradoxical growth increase after using GPA to prevent hypertension in three-week-old SHR.MethodsImplementing the “Animal Research: Reporting of In Vivo Experiments” (ARRIVE) guideline, male, three-week-old spontaneously hypertensive rats (N=22) were randomly assigned to standard soy-based (creatine-free) chow with GPA 0.1% vs control chow during four weeks (primary, t=4w) or six weeks of treatment (t=6w). Blood pressure measured by the tail-cuff method was the main outcome. Other outcomes included body mass and contractility characteristics of isolated arteries.Results Body mass at baseline was 28.4 (SE 0.71) g (n=22). With similar food intake/100 gram animal in both groups, GPA-treated rats (n=11) developed a strikingly larger body size and mass: t=4w, GPA 110.4 g (3.7) vs controls (n=11) 65.0 g (4.8) (+69.8%; p<0.001); t=6w, GPA 154.3 (4.7) vs controls 68.0 (4.7) g. There were no significant differences in cardiovascular parameters including blood pressure.DiscussionAn unexpected increase in body mass and size without concurrent blood pressure increase was observed in juvenile SHR on GPA vs control soy-based chow. It is speculated that the partial creatine agonist activity of GPA contributed to these effects. Further studies are needed to confirm these findings and better understand the impact of modulating energy metabolism in juvenile hypertension-prone mammals.

1447P Efficacy and toxicity profile of trans dermal buprenorphine for cancer pain management: Experience from a tertiary care center in northern India

Buprenorphine is partial agonist activity at the μ-opioid receptor and competitive antagonist activity at the kappa opioid receptor. Transdermal therapeutic system buprenorphine should be of special value in cancer pain control. Such a buprenorphine formulation allows for a stepwise dose increase, similar to that reported for sustained-release morphine. We evaluated the effectiveness and tolerability of transdermal buprenorphine (TDB) treatment for cancer pain management.

Molecular Docking Study of Mangosteen (Garcinia mangostana L.) Xanthone-Derived Isolates as Anti Androgen

Androgen receptor (AR) is the member of steroid hormone receptor involved in the progression of prostate cancer growth due to receptor over-activation. On the other hand, mangosteen (Garcinia mangostana L.) as a medicinal plant contains xanthone-derived compounds which were known to have cytotoxic activity towards any types of human cancer cells. This research aims to determine xanthone-derived isolates potency from mangosteen as AR antagonists. The study was carried out through molecular docking assay utilizing AutoDock 4.2.6 using androgen receptor obtained from PDB ID 2AM9, testosterone as native ligand, and bicalutamide, flutamide, and nilutamide as reference. The results indicated that three isolates (1,3,7-trihydroxy-2,8-di-(3-methylbut-2-enyl)xanthone, mangostinone, and trapezifolixanthone) have the highest potency to be AR antagonist seen from the lower bond-free energy value than all of reference ligand. The lowest bond-free energy was provided by mangostinone with a ΔG value of -10.05 kcal/mol. However, the highest difference of residual amino acids interaction with testosterone and similar interaction with bicalutamide was provided by 1,3,7-trihydroxy-2,8-di-(3-methylbut-2-enyl)xanthone, with five different amino acids with testosterone and nine similar amino acids with bicalutamide, respectively. Interestingly, 1,3,7-trihydroxy-2,8-di-(3-methylbut-2-enyl)xanthone has similar hydrogen bond with the key residue amino acids of AR (705-Asn and 711-Gln) which indicates probably partial agonist activity while mangostinone has the highest amount of hydrogen bond in the absence of hydrogen bond towards key residual amino acids of AR. The results concluded that three specific derived-xanthone compounds were predicted to have activity as AR antagonists.Keywords: Prostate cancer, Androgen receptor, Mangosteen, Xanthone, Molecular docking.