scholarly journals The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2640 ◽  
Author(s):  
Meining Wang ◽  
Thomas C. Irvin ◽  
Christine A. Herdman ◽  
Ramsey D. Hanna ◽  
Sergio A. Hassan ◽  
...  
Keyword(s):  
Partial Agonist ◽  
Squirrel Monkeys ◽  
The Body ◽  
In Vitro Assays ◽  
Potency Ratio ◽  
Gtpγs Binding ◽  
Potent Agonist ◽  
Optically Pure ◽  
Stimulation Of

(−)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). “Body” and “tail” interactions with opioid receptors (a subset of Portoghese’s message-address theory) were used for molecular modeling and simulations, where the “address” can be considered the “body” of the hydromorphone molecule and the “message” delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/μ potency ratio of 1.2 in the ([35S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.

Excitatory and inhibitory effects of gastrin peptides on gastric motility in sheep

1989 ◽  
Vol 257 (2) ◽  
pp. R388-R395 ◽  
Author(s):  
L. M. McLeay ◽  
M. H. Wong
Keyword(s):  
The Body ◽  
Inhibitory Effects ◽  
Cholinergic Neurones ◽  
Conscious Sheep ◽  
Nerve Muscle ◽  
Human Gastrin ◽  
Mixed Nerve ◽  
Stimulation Of

In conscious sheep, tetragastrin, pentagastrin, and synthetic human gastrin I, injected either subcutaneously or intravenously in doses of 156-5,200 pmol/kg body wt, inhibited the vagally dependent cyclical motility of the reticulum and rumen, whereas in vitro pentagastrin (10(-12) to 10(-6) M) had no demonstrable inhibitory or excitatory effects on intrinsically active or quiescent muscle of the reticulum, rumen, and omasal leaves. In vitro pentagastrin (10(-18) to 10(-4) M) stimulated quiescent and intrinsically active longitudinal and circular muscles of the body of the omasum and the body and antrum of the abomasum and potentiated contractile responses of antral muscle to electrical stimulation of intramural cholinergic nerves. Responses in the presence of hexamethonium, atropine, and tetrodotoxin indicated that the excitatory effects on mixed nerve-muscle preparations of omasal and abomasal tissue were mediated both through stimulation of cholinergic neurones and by direct actions on the muscle. In vitro the ovine stomach shows marked regional differences in both its response and sensitivity to gastrin peptides, and their inhibitory effects on reticuloruminal motility in vivo appear to be other than direct.

scholarly journals Identification of new gonadotrophin-releasing hormone partial agonists

2006 ◽  
Vol 189 (3) ◽  
pp. 509-517 ◽  
Author(s):  
Alfredo Leaños-Miranda ◽  
Alfredo Ulloa-Aguirre ◽  
Laura A Cervini ◽  
Jo Ann Janovick ◽  
Jean Rivier ◽  
...  
Keyword(s):  
Inositol Phosphate ◽  
Partial Agonist ◽  
Prolonged Treatment ◽  
Complete Suppression ◽  
Antagonist Activity ◽  
Gnrh Analogues ◽  
Full Agonist ◽  
Partial Agonists ◽  
Stimulation Of

GnRH agonists or antagonists are currently utilized as therapeutic agents in a number of diseases. A side-effect of prolonged treatment with GnRH analogues is hypoestrogenism. In this study, we tested the in vitro potency of different GnRH analogues originally found to be partial agonists (i.e. analogues with decreased efficacy for activating or stimulating their cognate receptor) as well as novel analogues, to identify compounds that might potentially be useful for partial blockade of gonadotrophin release. Cultured COS-7 cells transiently expressing the rat or human GnRH receptor (GnRHR) were exposed to increasing concentrations (10−8 to 10−5 M) of GnRH analogues (c(4–10)[Asp4,DNal6,Dpr10]-GnRH; c(4–10) [Dpr4,DNal6,Asp10]-GnRH; c(4–10)[Cys4,10,DNal6]-GnRH; c[Eaca1,DNal6]-GnRH; c[Gly1,DNal6]-GnRH; c[βAla1,DTrp6]-GnRH; c[Dava1,DNal6]-GnRH; c[Gaba1, DNal6]-GnRH), and the ability of these analogues to provoke or antagonize GnRH-stimulated inositol phosphate production was assessed. With both human and rat GnRHRs, c[Eaca1,DNal6]-GnRH, c[Gly1,DNal6]-GnRH, c[βAla1,DTrp6]-GnRH and c[Dava1,DNal6]-GnRH exhibited partial agonist activity (35–87% of the maximal efficacy shown by 10−6 M GnRH), whereas c[Gaba1,DNal6]-GnRH behaved as a partial agonist with the human GnRHR and as full agonist with the rat GnRHR. c(4–10)[Asp4, DNal6,Dpr10]-GnRH and c(4–10)[Dpr4,DNal6,Asp10]-GnRH exhibited full antagonist activity with both GnRHRs, and c(4–10) [Cys4,10,DNal6]-GnRH was a weak, partial agonist with the human GnRHR and a full antagonist with the rat GnRHR. With the exception of c[Gaba1,DNal6]-GnRH stimulation of the human GnRHR, and c[Dava1,DNal6]-GnRH and c[Gaba1, DNal6]-GnRH stimulation of the rat GnRHR, all partial agonists also exhibited antagonist activity in the presence of the exogenous full agonist. The results demonstrate that structurally similar analogues display variable potencies and efficacies in vitro for a specific GnRHR as well as for the human versus the rat GnRHR. Their ultimate in vivo usefulness to treat clinical conditions in which complete suppression of gonadotroph activity is not required remains to be investigated.

scholarly journals Leveraging Nuclear Receptors as Targets for Pathological Ocular Vascular Diseases

2020 ◽  
Vol 21 (8) ◽  
pp. 2889 ◽  
Author(s):  
Pei-Li Yao ◽  
Jeremy Peavey ◽  
Goldis Malek
Keyword(s):  
Nuclear Receptors ◽  
Vascular Diseases ◽  
The Body ◽  
Age Related Macular Degeneration ◽  
In Vitro Assays ◽  
In Vivo Models ◽  
Age Related ◽  
Vessel Growth

Vasculogenesis and angiogenesis are physiological mechanisms occurring throughout the body. Any disruption to the precise balance of blood vessel growth necessary to support healthy tissue, and the inhibition of abnormal vessel sprouting has the potential to negatively impact stages of development and/or healing. Therefore, the identification of key regulators of these vascular processes is critical to identifying therapeutic means by which to target vascular-associated compromises and complications. Nuclear receptors are a family of transcription factors that have been shown to be involved in modulating different aspects of vascular biology in many tissues systems. Most recently, the role of nuclear receptors in ocular biology and vasculopathies has garnered interest. Herein, we review studies that have used in vitro assays and in vivo models to investigate nuclear receptor-driven pathways in two ocular vascular diseases associated with blindness, wet or exudative age-related macular degeneration, and proliferative diabetic retinopathy. The potential therapeutic targeting of nuclear receptors for ocular diseases is also discussed.

scholarly journals Evidence of the hypoglycemic capacity of some natural products for the alternative treatment of diabetes mellitus type 2

2020 ◽  
Vol 8 (16) ◽  
pp. 56-64
Author(s):  
Karla Guadalupe Perez-Avila ◽  
Cruz Vargas-De-León ◽  
José Antonio Morales-González ◽  
Eduardo Madrigal-Santillán
Keyword(s):  
Diabetes Mellitus ◽  
Natural Products ◽  
Alternative Treatment ◽  
The Body ◽  
In Vitro Assays ◽  
Glucose Levels ◽  
Natural Treatment ◽  
Treatment Of Diabetes

Diabetes mellitus is a disease that is characterized by the chronic presence of blood glucose levels caused by a defect in the secretion of insulin or in the action of this hormone in the body which must be treated integrally with a multidisciplinary approach. The natural treatment of this disease is a common practice around the world, especially in Latin America, there are several clinical studies, in vivo or in vitro assays that focus on assessing the hypoglycemic capacity of various natural products used empirically by the population for years for the phytotherapeutic treatment of the disease as well as the chemicals related to the mechanism of action that produces the hypoglycaemic effect. In the present article, a brief review of the evidence of the hypoglycemic capacity of some natural products for the alternative treatment of diabetes mellitus 2

Inhibition of nitric oxide synthesis improves detoxication in inflammatory liver dysfunction in vivo

1997 ◽  
Vol 273 (2) ◽  
pp. G530-G536 ◽  
Author(s):  
A. Veihelmann ◽  
T. Brill ◽  
M. Blobner ◽  
I. Scheller ◽  
B. Mayer ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
In Vitro Assays ◽  
Serum Concentrations ◽  
Aminopyrine Breath Test ◽  
Vitro Assay ◽  
Synthase Inhibitor ◽  
Cytochrome P 450 ◽  
Stimulation Of

Inflammatory stimulation of the liver induces nitric oxide (NO) biosynthesis and suppression of detoxication. In this study the effect of NO biosynthesis on cytochrome P-450 (CYP) enzyme activity was investigated by comparing in vivo and in vitro assays. To establish liver inflammation, CD rats were injected with Corynebacterium parvum (C. parvum) suspension. After 5 days NO biosynthesis was highly induced as indicated by increased NO2- plus NO3- serum concentrations. At the same time the aminopyrine breath test (ABT), measuring CYP activity in vivo, was reduced to 42% and the in vitro assay of aminopyrine turnover was suppressed to 12% of NaCl- injected controls. When C. parvum-injected animals were treated with the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA), CYP activities significantly improved with an ABT of 76% and an in vitro aminopyrine turnover of 47% of controls. Neither C. parvum injections nor L-NMMA treatment resulted in a significant change of CYP protein concentrations. These data indicate that suppression of xenobiotic metabolism can be attenuated by inhibition of NO biosynthesis during an ongoing process of inflammation.

scholarly journals Prediction of Drug-Induced Hyperbilirubinemia by In Vitro Testing

Pharmaceutics ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 755
Author(s):  
Péter Tátrai ◽  
Péter Krajcsi
Keyword(s):  
Organic Anion ◽  
The Body ◽  
In Vitro Assays ◽  
Current Evidence ◽  
Drug Induced ◽  
Organic Anion Transporting Polypeptide ◽  
Resistance Protein ◽  
Clinically Significant ◽  
Uptake Transporters

Bilirubin, the end product of heme catabolism, is produced continuously in the body and may reach toxic levels if accumulates in the serum and tissues; therefore, a highly efficient mechanism evolved for its disposition. Normally, unconjugated bilirubin enters hepatocytes through the uptake transporters organic anion transporting polypeptide (OATP) 1B1 and 1B3, undergoes glucuronidation by the Phase II enzyme UDP glucuronosyltransferase 1A1 (UGT1A1), and conjugated forms are excreted into the bile by the canalicular export pump multidrug resistance protein 2 (MRP2). Any remaining conjugated bilirubin is transported back to the blood by MRP3 and passed on for uptake and excretion by downstream hepatocytes or the kidney. The bile salt export pump BSEP as the main motor of bile flow is indirectly involved in bilirubin disposition. Genetic mutations and xenobiotics that interfere with this machinery may impede bilirubin disposition and cause hyperbilirubinemia. Several pharmaceutical compounds are known to cause hyperbilirubinemia via inhibition of OATP1Bs, UGT1A1, or BSEP. Herein we briefly review the in vitro prediction methods that serve to identify drugs with a potential to induce hyperbilirubinemia. In vitro assays can be deployed early in drug development and may help to minimize late-stage attrition. Based on current evidence, drugs that behave as mono- or multispecific inhibitors of OATP1B1, UGT1A1, and BSEP in vitro are at risk of causing clinically significant hyperbilirubinemia. By integrating inhibition data from in vitro assays, drug serum concentrations, and clinical reports of hyperbilirubinemia, predictor cut-off values have been established and are provisionally suggested in this review. Further validation of in vitro readouts to clinical outcomes is expected to enhance the predictive power of these assays.

Partial agonist efficacy of EMD386088, a 5-HT6 receptor ligand, in functional in vitro assays

2013 ◽  
Vol 65 (4) ◽  
pp. 998-1005 ◽  
Author(s):  
Magdalena Jastrzębska-Więsek ◽  
Agata Siwek ◽  
Grzegorz Kazek ◽  
Barbara Nawieoeniak ◽  
Anna Partyka ◽  
...  
Keyword(s):  
Partial Agonist ◽  
In Vitro Assays ◽  
Receptor Ligand

Oleanolic acid derivative HA-20 inhibits adipogenesis in a manner involving PPARγ-FABP4/aP2 pathway

2021 ◽  
Author(s):  
Jie Wang ◽  
Yuchao Zhang ◽  
Qi Shen ◽  
Jing Wu ◽  
Jian-Xin Li
Keyword(s):  
Oleanolic Acid ◽  
Early Stage ◽  
Heart Diseases ◽  
The Body ◽  
In Vivo Studies ◽  
Lipid Lowering ◽  
In Vitro Assays ◽  
Mechanism Study

Obesity is a chronic disease that increases the risk of type II diabetes, heart diseases and nonalcoholic fatty liver disease. Unfortunately, to date, only handful of drugs are approved for clinical use. This study aims at discovery of anti-obesity agents based on naturally sourced oleanolic acid (OA) derivatives. 3T3-L1 preadipocytes were differentiated into mature adipocytes for in vitro assays, and a high fat diet (HFD) induced obesity mice model was established for in vivo studies. The screening of the OA derivatives was performed with 3T3-L1 cell, and resulted in a discovery of a novel compound HA-20 with a potent inhibitory activity on 3T3-L1 adipogenesis. In vitro data demonstrated that HA-20 markedly suppressed the adipogenesis in 3T3-L1 at the early stage without cytotoxicity. In vivo research using HFD mice revealed that HA-20 lowered the body weight, and possessed a lipid-lowering effect. Transcriptome analysis discovered that the mainly adipogenesis/lipogenesis genes regulated by HA-20 were PPARγ, C/EBPα, Fas, ACC, and Fabp4/aP2. Mechanism study revealed that HA-20 played its bioactive roles at least via downregulating PPARγ-FABP4/aP2 pathway in 3T3-L1, which was further confirmed in HFD induced obesity mice. Our findings provided a new insight into fighting fat accumulation based on OA derivatives, and demonstrated that HA-20 may sever as a worthy leading compound for further development of anti-obesity agents.

scholarly journals Two Extracts From Manihot Esculenta Leaves Efficiently Inhibit α-Glucosidase and α-Amylase: A New Approach for the Management of Diabetes

2020 ◽  
Vol 14 (3) ◽  
pp. 131-138
Author(s):  
Israel Oghenevwodokohwo Okoro ◽  
Keyword(s):  
Manihot Esculenta ◽  
Ethanol Extract ◽  
Acetone Extract ◽  
The Body ◽  
Total Flavonoid ◽  
In Vitro Assays ◽  
Manihot Esculenta Crantz ◽  
Phenolic Contents ◽  
Health And Disease

Background: In Nigeria, the leaves of Manihot esculenta (Crantz) are eaten as vegetables. The leaves are rich in phytochemicals, valuable and natural sources of antioxidants, and are highly useful for human health and disease prevention. This study was aimed to evaluate the in vitro inhibitory effects of two extracts derived from the plant leaves on α-glucosidase and α-amylase. The total flavonoid and phenolic contents of the extracts were also assessed. Methods: The leaves of M. esculenta were processed and extracted with ethanol and acetone. The extracts were evaluated for their α-glucosidase and α-amylase inhibitory activities. Also, their total flavonoid and phenolic contents were determined, using standard in vitro assays. Results: The ethanol extract exhibited a higher α-glucosidase and α-amylase inhibitory activity than the acetone extract, which positively correlated with their total flavonoid and phenolic contents. In addition, the ethanol extract strongly inhibited the α-glucosidase activity (IC50: 0.77±0.03 mg/mL) than Acarbose (IC50: 1.52±0.14 mg/mL). However, both extracts of ethanol (IC50: 1.29±0.02 mg/mL) and acetone (IC50 1.66±0.05 mg/mL) were less effective in inhibiting α-amylase compared with that of Acarbose (IC50 0.99±0.02 mg/mL). Comparatively, the percent inhibition of the extracts and Acarbose were in this order: ethanol extract > Acarbose > acetone extract. Conclusion: The results suggest that the extract of M. esculenta leaves have anti-hyperglycemic effects. They are potential alternative antioxidants that could be used to reduce oxidative stress in the body and in the management of diabetes.

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