Reductions in log P Improved Protein Binding and Clearance Predictions Enabling the Prospective Design of Cannabinoid Receptor (CB1) Antagonists with Desired Pharmacokinetic Properties

2013 ◽  
Vol 56 (23) ◽  
pp. 9586-9600 ◽  
Author(s):  
Bruce A. Ellsworth ◽  
Philip M. Sher ◽  
Ximao Wu ◽  
Gang Wu ◽  
Richard B. Sulsky ◽  
...  
Keyword(s):  
Protein Binding ◽  
Cannabinoid Receptor ◽  
Log P ◽  
Prospective Design ◽  
Pharmacokinetic Properties ◽  
Cb1 Antagonists

scholarly journals Prediction of Biopharmaceutical Drug Disposition Classification System (BDDCS) by Structural Parameters

2019 ◽  
Vol 22 ◽  
pp. 247-269 ◽  
Author(s):  
Yeganeh Golfar ◽  
Ali Shayanfar
Keyword(s):  
Classification System ◽  
Drug Disposition ◽  
Structural Parameters ◽  
Log P ◽  
Metabolizing Enzymes ◽  
Acceptable Accuracy ◽  
Water Partition Coefficient ◽  
Pharmacokinetic Properties ◽  
Solvation Parameters ◽  
External Test

Modeling of physicochemical and pharmacokinetic properties is important for the prediction and mechanism characterization in drug discovery and development. Biopharmaceutics Drug Disposition Classification System (BDDCS) is a four-class system based on solubility and metabolism. This system is employed to delineate the role of transporters in pharmacokinetics and their interaction with metabolizing enzymes. It further anticipates drug disposition and potential drug-drug interactions in the liver and intestine. According to BDDCS, drugs are classified into four groups in terms of the extent of metabolism and solubility (high and low). In this study, structural parameters of drugs were used to develop classification-based models for the prediction of BDDCS class. Reported BDDCS data of drugs were collected from the literature, and structural descriptors (Abraham solvation parameters and octanol–water partition coefficient (log P)) were calculated by ACD/Labs software. Data were divided into training and test sets. Classification-based models were then used to predict the class of each drug in BDDCS system using structural parameters and the validity of the established models was evaluated by an external test set. The results of this study showed that log P and Abraham solvation parameters are able to predict the class of solubility and metabolism in BDDCS system with good accuracy. Based on the developed methods for prediction solubility and metabolism class, BDDCS could be predicted in the correct with an acceptable accuracy. Structural properties of drugs, i.e. logP and Abraham solvation parameters (polarizability, hydrogen bonding acidity and basicity), are capable of estimating the class of solubility and metabolism with an acceptable accuracy.

Diffusion of Drugs into Prostatic Fluid and Milk

1974 ◽  
Vol 8 (8) ◽  
pp. 470-475 ◽  
Author(s):  
Eric J. Lien ◽  
Jean Kuwahara ◽  
Robert T. Koda
Keyword(s):  
Protein Binding ◽  
Partition Coefficient ◽  
Blood Circulation ◽  
Antibacterial Agents ◽  
Log P ◽  
Clinical Implications ◽  
Degree Of Dissociation ◽  
Ph Values ◽  
Prostatic Fluid ◽  
Plasma Concentration Ratio

THE PROSTATIC FLUID/PLASMA CONCENTRATION RATIO of various sulfonamides, antibiotics and antibacterial agents, and the milk/plasma ratio of sulfonamides and basic drugs have been quantitatively correlated with the degree of dissociation, as represented by log U/D, and the partition coefficient (log P). Because of the lower pH values of the prostatic fluid (6.6) and milk (6.8) as compared with the plasma pH (7.4), the degree of dissociation appears to be the most important factor in determining the distribution of these weak acids or bases. Partition coefficient also plays a secondary role. The log Po for maximum diffusion into milk is lower than that for maximum gastrointestinal, buccal or percutaneous absorption. This may be attributed to plasma protein binding which prevents diffusion of the drug from the blood circulation into the milk since high lipophilicity favors protein binding. The clinical implications of the correlations obtained are discussed.

scholarly journals Towards rational design of cannabinoid receptor 1 (CB1) antagonists for peripheral selectivity

2011 ◽  
Vol 21 (19) ◽  
pp. 5711-5714 ◽  
Author(s):  
Alan Fulp ◽  
Katherine Bortoff ◽  
Yanan Zhang ◽  
Herbert Seltzman ◽  
Rodney Snyder ◽  
...  
Keyword(s):  
Rational Design ◽  
Cannabinoid Receptor ◽  
Cannabinoid Receptor 1 ◽  
Cb1 Antagonists

The Endocannabinoid System and Alcohol Dependence: Will Cannabinoid Receptor 2 Agonism be More Fruitful than Cannabinoid Receptor 1 Antagonism?

2021 ◽  
Vol 20 ◽  
Author(s):  
Aboagyewaah Oppong-Damoah ◽  
Brenda Marie Gannon ◽  
Kevin Sean Murnane
Keyword(s):  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Health Concern ◽  
Cb2 Receptor ◽  
Neuroprotective Effects ◽  
Receptor Agonists ◽  
Clinical Phase ◽  
Anti Inflammatory ◽  
Cb1 Antagonists ◽  
Psychiatric Side Effects

: Alcohol-use disorder (AUD) remains a major public health concern. In recent years, there has been a heightened interest in components of the endocannabinoid system for the treatment of AUD. Cannabinoid type 1 (CB1) receptors have been shown to modulate the rewarding effects of alcohol, reduce the abuse-related effects of alcohol, improve cognition, exhibit anti-inflammatory, and neuroprotective effects, which are all favorable properties of potential therapeutic candidates for the treatment of AUD. However, CB1 agonists have not been investigated for the treatment of AUD because they stimulate the motivational properties of alcohol, increase alcohol intake, and have the tendency to be abused. Preclinical data suggest significant potential for the use of CB1 antagonists to treat AUD; however, a clinical phase I/II trial with SR14716A (rimonabant), a CB1 receptor antagonist/inverse agonist showed that it produced serious neuropsychiatric adverse events such as anxiety, depression, and even suicidal ideation. This has redirected the field to focus on alternative components of the endocannabinoid system, including cannabinoid type 2 (CB2) receptor agonists as a potential therapeutic target for AUD. CB2 receptor agonists are of particular interest because they can modulate the reward pathway, reduce abuse-related effects of alcohol, reverse neuroinflammation, improve cognition, and exhibit anti-inflammatory and neuroprotective effects, without exhibiting the psychiatric side effects seen with CB1 antagonists. Accordingly, this article presents an overview of the studies reported in the literature that have investigated CB2 receptor agonists with regards to AUD and provides commentary as to whether this receptor is a worthy target for continued investigation.

scholarly journals Structure-Based Identification of Potent Natural Product Chemotypes as Cannabinoid Receptor 1 Inverse Agonists

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2630 ◽  
Author(s):  
Pankaj Pandey ◽  
Kuldeep Roy ◽  
Haining Liu ◽  
Guoyi Ma ◽  
Sara Pettaway ◽  
...  
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Binding Affinity ◽  
Cannabinoid Receptor ◽  
New Drugs ◽  
In Vitro Screening ◽  
Cannabinoid Receptor 1 ◽  
Cardiometabolic Disorders ◽  
Cb1 Antagonists

Natural products are an abundant source of potential drugs, and their diversity makes them a rich and viable prospective source of bioactive cannabinoid ligands. Cannabinoid receptor 1 (CB1) antagonists are clinically established and well documented as potential therapeutics for treating obesity, obesity-related cardiometabolic disorders, pain, and drug/substance abuse, but their associated CNS-mediated adverse effects hinder the development of potential new drugs and no such drug is currently on the market. This limitation amplifies the need for new agents with reduced or no CNS-mediated side effects. We are interested in the discovery of new natural product chemotypes as CB1 antagonists, which may serve as good starting points for further optimization towards the development of CB1 therapeutics. In search of new chemotypes as CB1 antagonists, we screened the in silico purchasable natural products subset of the ZINC12 database against our reported CB1 receptor model using the structure-based virtual screening (SBVS) approach. A total of 18 out of 192 top-scoring virtual hits, selected based on structural diversity and key protein–ligand interactions, were purchased and subjected to in vitro screening in competitive radioligand binding assays. The in vitro screening yielded seven compounds exhibiting >50% displacement at 10 μM concentration, and further binding affinity (Ki and IC50) and functional data revealed compound 16 as a potent and selective CB1 inverse agonist (Ki = 121 nM and EC50 = 128 nM) while three other compounds—2, 12, and 18—were potent but nonselective CB1 ligands with low micromolar binding affinity (Ki). In order to explore the structure–activity relationship for compound 16, we further purchased compounds with >80% similarity to compound 16, screened them for CB1 and CB2 activities, and found two potent compounds with sub-micromolar activities. Most importantly, these bioactive compounds represent structurally new natural product chemotypes in the area of cannabinoid research and could be considered for further structural optimization as CB1 ligands.

Synthesis, Radiolabeling, and Characterization of Plasma Protein-Binding Ligands: Potential Tools for Modulation of the Pharmacokinetic Properties of (Radio)Pharmaceuticals

2017 ◽  
Vol 28 (9) ◽  
pp. 2372-2383 ◽  
Author(s):  
Cristina Müller ◽  
Renáta Farkas ◽  
Francesca Borgna ◽  
Raffaella M. Schmid ◽  
Martina Benešová ◽  
...  
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Pharmacokinetic Properties

scholarly journals The In vitro Effects of Atenolol and Zinc Chloride on the Protein Binding of Amlodipine in Aqueous Medium

1970 ◽  
Vol 7 (1) ◽  
pp. 15-21 ◽  
Author(s):  
Md Shah Amran ◽  
Sheikh Niaz Morshed ◽  
Md Jahangir Alam Khandakar ◽  
Md Masudur Rahman ◽  
Md Mosiur Rahman ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Protein Binding ◽  
Zinc Chloride ◽  
Equilibrium Dialysis ◽  
In Vitro Study ◽  
Pharmacokinetic Properties ◽  
Number Of Binding Sites ◽  
Dialysis Method ◽  
Tissue Systems

An in vitro study of protein binding has been carried out to observe the influence of atenolol and zinc chloride on the protein binding of amlodipine by equilibrium dialysis method at 37±1 0C and at physiological pH (7.4). It has been found that zinc chloride lowered the affinity and percentage of protein binding of amlodipine to bovine serum albumin but atenolol has no such effect. The Scatchard plots were prepared to reveal the number of binding sites and the affinity for protein binding. It was seen that the highest percentage binding of amlodipine was 91% and the lowest was 74%. In the presence of atenolol, the highest and the lowest value of percentage of protein binding was 90% and 72%, respectively. In the presence of zinc chloride these values were 84% and 65% respectively. It is, thus, inferred that atenolol or its complex with amlodipine has no significant effect on percentage of protein binding of amlodipine. While zinc chloride or its complex with amlodipine can cause a decrease in percentage of protein binding of amlodipine. Complexation of amlodipine with zinc chloride might, therefore, displace the drug from the plasma and the displaced drugs may be redistributed, thus , increasing the free drug in plasma and tissue systems. This may change the pharmacokinetic properties of the drug and may affect the pharmacological and toxic effects. It is thus inferred that care and monitoring must be taken during combination therapy of amlodipine and zinc chloride. Key words: Amlodipine, protein binding, binding site, equilibrium dialysis, Scatchard plot, atenolol, zinc chloride, combination therapy  DOI = 10.3329/dujps.v7i1.1202Dhaka Univ. J. Pharm. Sci. 7(1): 15-21, 2008 (June)

scholarly journals In vitro membrane binding and protein binding (IAM MB/PB technology) to estimate in vivo distribution: applications in early drug discovery

ADMET & DMPK ◽  
2017 ◽  
Vol 5 (1) ◽  
pp. 14 ◽  
Author(s):  
Klara Livia Valko ◽  
Simon P. Teague ◽  
Charles Pidgeon
Keyword(s):  
Drug Discovery ◽  
Protein Binding ◽  
Specific Binding ◽  
Efficiency Index ◽  
Log P ◽  
Basic Principles ◽  
In Vivo Distribution ◽  
Drug Efficiency

<p class="ADMETabstracttext">The drug discovery process can be accelerated by chromatographic profiling of the analogs to model in vivo distribution and the major non-specific binding. A balanced potency and chromatographically determined membrane and protein binding (IAM MB/PB) data enable selecting drug discovery compounds for further analysis that have the highest probability to show the desired in vivo distribution behavior for efficacy and reduced chance for toxicity. Although the basic principles of the technology have already appeared in numerous publications, the lack of standardized procedures limited its widespread applications especially in academia and small drug discovery biotech companies. In this paper, the standardized procedures are described that has been trademarked as Regis IAM MB/PB Technology®. Comparison between the Drug Efficiency Index (DEI=pIC50-logVdu+2) and generally used Ligand Lipophilicity Efficiency (LLE) has been made, demonstrating the advantage of measured IAM and HSA binding over calculated log P. The power of the proposed chromatographic technology is demonstrated using the data of marketed drugs.</p>

scholarly journals Resistance to epinephrine and hypersensitivity (hyperresponsiveness) to CB1 antagonists in a patient with pseudohypoparathyroidism type Ic

2010 ◽  
Vol 162 (4) ◽  
pp. 819-824 ◽  
Author(s):  
Abdallah Al-Salameh ◽  
F Despert ◽  
Marie-Laure Kottler ◽  
Agnès Linglart ◽  
Jean-Claude Carel ◽  
...  
Keyword(s):  
Cannabinoid Receptor ◽  
Normal Activity ◽  
Response To Treatment ◽  
Melanocortin 4 Receptor ◽  
Cb1 Antagonist ◽  
Disorder Treatment ◽  
Cb1 Antagonists ◽  
Gnas Mutation

Pseudohypoparathyroidism (PHP) covers a heterogeneous group of disorders, which have in common resistance to parathyroid hormone (PTH). However, they differ in many aspects such as site of the defect in signal transduction, clinical picture (with or without Albright's hereditary osteodystrophy (AHO)), extension of hormone resistance, and the tissue activity of protein Gs. PHP type Ic, a rare subtype, is characterized by resistance to several hormones, the presence of AHO, and normal activity of protein Gs. We present the case of a patient with PHP type Ic. Although resistance to TSH was suggested at the age of 12 months, diagnosis was made when she presented with hypocalcemia and resistance to PTH. Resistance to GH was also detected, and partial resistance to gonadotropins became clear after puberty. We demonstrated a defective lipolytic response to epinephrine, suggesting a role of this resistance in the pathogenesis of her morbid obesity. In view of the difficulties in the management of overweight in this disorder, treatment with a cannabinoid receptor type 1 (CB1) antagonist was started, and it proved to be highly effective, lowering the patient's body mass index from 40.5 to 33.5, which was quite impressive. We propose that an underactive melanocortin-4 receptor, which is found in certain patients with PHP, leads to upregulation of the CB1 receptor and consequently to a good response to treatment with CB1 antagonists. Another interesting finding was the GNAS mutation that was identified in this patient. A nonsense mutation resulted in a truncated Gsa that was able to stimulate adenylyl cyclase efficiently, but could not bind to receptors in a normal way.

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