Last update 01 Nov 2024

COX-1 x FAAH x COX-2

Last update 01 Nov 2024

Basic Info

Related Targets

COX-1FAAHCOX-2

Drugs associated with COX-1 x FAAH x COX-2

Carprofen

Target

COX-1 x COX-2 x FAAH

Mechanism

COX-1 inhibitors [+2]

Active Org.

Istituto Italiano di Tecnologia

Originator Org.

F. Hoffmann-La Roche Ltd.

Active Indication

Inflammation [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.

First Approval Date31 Dec 1987

100 Clinical Results associated with COX-1 x FAAH x COX-2

100 Translational Medicine associated with COX-1 x FAAH x COX-2

0 Patents (Medical) associated with COX-1 x FAAH x COX-2

Literatures (Medical) associated with COX-1 x FAAH x COX-2

01 Jun 2024·Naunyn-Schmiedeberg's Archives of Pharmacology

Interaction of endocannabinoid system and cyclooxygenase metabolites with fatty acid amide hydrolase and cyclooxygenase enzyme activities on contractile responses in rat vas deferens tissue

Article

Author: Ozturk Fincan, Gokce Sevim ; Okcay, Yagmur ; Vural, Elif Hilal ; Askin, Celil Ilker ; Gudul Bacanli, Merve ; Vural, Ismail Mert

The endocannabinoid system and prostaglandins are important modulators in the genitourinary system. This study aimed to investigate the possible interactions between the endocannabinoid system and the cyclooxygenase (COX) pathway on rat vas deferens. For this purpose, the concentration responses of the endocannabinoid anandamide, prostaglandin F_2α analog latanoprost, and prostaglandin E₁ analog misoprostol on the electrical field stimulation (EFS)-induced contractile responses were obtained. The concentration responses to anandamide were obtained again in the presence of nonselective COX inhibitor flurbiprofen and prostaglandin analogs, while the concentration responses of latanoprost and misoprostol were obtained in the presence of cannabinoid receptor antagonists and fatty acid amide hydrolase (FAAH) enzyme inhibitor URB597. FAAH, COX-1, and COX-2 enzyme levels in vas deferens tissue samples were also determined. The cumulative addition of anandamide was not different from the vehicle; however, the EFS-induced contractile responses were significantly increased with the incubation of latanoprost or flurbiprofen in the prostatic portion. Flurbiprofen and misoprostol decreased FAAH enzyme levels in both portions of the vas deferens, while latanoprost induced the inhibition in the prostatic portion. The cumulative administration of latanoprost and misoprostol significantly enhanced the contractile responses in the prostatic portion. This effect of latanoprost was significantly antagonized by URB597 and AM251. The enhancing effect of misoprostol was antagonized by anandamide, URB597, AM251, and AM630. Anandamide, AM251, AM630, and URB597 decreased enzyme levels of COX-1 and COX-2 in both portions of the vas deferens. These results demonstrate an intricate crosstalk between endocannabinoids and prostaglandins in modulation of the vas deferens contractility.

01 Sep 2022·Journal of Molecular Modeling

CB1 as a novel target for Ginkgo biloba’s terpene trilactone for controlling chemotherapy-induced peripheral neuropathy (CIPN)

Article

Author: Chamani, Jamshidkhan ; Saberi, Mohammad Reza ; Samandar, Farzaneh ; Tehranizadeh, Zeinab Amiri

The application of antineoplastic chemotherapeutic agents causes a common side effect known as chemotherapy-induced peripheral neuropathy (CIPN) that leads to reducing the quality of patient's life. This research involves the performance of molecular docking and molecular dynamic (MD) simulation studies to explore the impact of terpenoids of Ginkgo biloba on the targets (CB-1, TLR4, FAAH-1, COX-1, COX-2) that can significantly affect the controlling of CIPN's symptoms. According to the in-vitro and in-vivo investigations, terpenoids, particularly ginkgolides B, A, and bilobalide, can cause significant effects on neuropathic pain. The molecular docking results disclosed the tendency of our ligands to interact with mainly CB1 and FAAH-1, as well as partly with TLR4, throughout their interactions with targets. Terpene trilactone can exhibit a lower rate of binding energy than CB1's inhibitor (7dy), while being precisely located in the CB1's active site and capable of inducing stable interactions by forming hydrogen bonds. The analyses of MD simulation proved that ginkgolide B was a more suitable activator and inhibitor for CB1 and TLR4, respectively, when compared to bilobalide and ginkgolide A. Moreover, bilobalide is capable of inhibiting FAAH-1 more effectively than the two other ligands. According to the analyses of ADME, every three ligands followed the Lipinski's rule of five. Considering these facts, the exertion of three ligands is recommended for their anti-inflammatory, neuroprotective, and anti-nociception influences caused by primarily activating CB1 and inhibiting FAAH-1 and TLR4; in this regard, these compounds can stand as potential candidates for the control and treatment of CIPN's symptoms.

02 Oct 2021·Temperature

Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action

Review

Author: Ayoub, Samir S

Paracetamol (acetaminophen) is undoubtedly one of the most widely used drugs worldwide. As an over-the-counter medication, paracetamol is the standard and first-line treatment for fever and acute pain and is believed to remain so for many years to come. Despite being in clinical use for over a century, the precise mechanism of action of this familiar drug remains a mystery. The oldest and most prevailing theory on the mechanism of analgesic and antipyretic actions of paracetamol relates to the inhibition of CNS cyclooxygenase (COX) enzyme activities, with conflicting views on the COX isoenzyme/variant targeted by paracetamol and on the nature of the molecular interactions with these enzymes. Paracetamol has been proposed to selectively inhibit COX-2 by working as a reducing agent, despite the fact that in vitro screens demonstrate low potency on the inhibition of COX-1 and COX-2. In vivo data from COX-1 transgenic mice suggest that paracetamol works through inhibition of a COX-1 variant enzyme to mediate its analgesic and particularly thermoregulatory actions (antipyresis and hypothermia). A separate line of research provides evidence on potentiation of the descending inhibitory serotonergic pathway to mediate the analgesic action of paracetamol, but with no evidence of binding to serotonergic molecules. AM404 as a metabolite for paracetamol has been proposed to activate the endocannabinoid and the transient receptor potential vanilloid-1 (TRPV1) systems. The current review gives an update and in some cases challenges the different theories on the pharmacology of paracetamol and raises questions on some of the inadequately explored actions of paracetamol. List of Abbreviations: AM404, N-(4-hydroxyphenyl)-arachidonamide; CB1R, Cannabinoid receptor-1; Cmax, Maximum concentration; CNS, Central nervous system; COX, Cyclooxygenase; CSF, Cerebrospinal fluid; ED₅₀, 50% of maximal effective dose; FAAH, Fatty acid amidohydrolase; IC₅₀, 50% of the maximal inhibitor concentration; LPS, Lipopolysaccharide; NSAIDs, Non-steroidal anti-inflammatory drugs; PGE₂, Prostaglandin E₂; TRPV1, Transient receptor potential vanilloid-1.

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