Novel bioactive metabolites of dipyrone (metamizol).

Dipyrone is a common antipyretic drug and the most popular non-opioid analgesic in many countries. In spite of its long and widespread use, molecular details of its fate in the body are not fully known. We administered dipyrone orally to mice. Two unknown metabolites were found, viz. the arachidonoyl amides of the known major dipyrone metabolites, 4-methylaminoantipyrine (2) and 4-aminoantipyrine (3). They were identified by ESI-LC-MS/MS after extraction from the CNS, and comparison with reference substances prepared synthetically. The arachidonoyl amides were positively tested for cannabis receptor binding (CB(1) and CB(2)) and cyclooxygenase inhibition (COX-1 and COX-2 in tissues and as isolated enzymes), suggesting that the endogenous cannabinoid system may play a role in the effects of dipyrone against pain.

Drugs, their targets and the nature and number of drug targets.

What is a drug target? And how many such targets are there? Here, we consider the nature of drug targets, and by classifying known drug substances on the basis of the discussed principles we provide an estimation of the total number of current drug targets.

New analgesics synthetically derived from the paracetamol metabolite N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide.

N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide (AM404) is a metabolite of the well-known analgesic paracetamol. AM404 inhibits endocannabinoid cellular uptake, binds weakly to CB1 and CB2 cannabinoid receptors, and is formed by fatty acid amide hydrolase (FAAH) in vivo. We prepared three derivatives of this new (endo)cannabinoid using bioisosteric replacement (1), homology (2), and derivatization (3) of the 4-aminophenol moiety in AM404 and tested them against CB1, CB2, and FAAH. We found affinities toward both cannabinoid receptors equal to or greater than that of AM404. Shortening the acyl chain from C20 to C2 led to three new paracetamol analogues: N-(1H-indazol-5-yl)acetamide (5), N-(4-hydroxybenzyl)acetamide (6), and N-(4-hydroxy-3-methoxyphenyl)acetamide (7). Again, 5, 6, and 7 were tested against CB1, CB2, and FAAH without significant activity. However, 5 and 7 behaved like inhibitors of cyclooxygenases in whole blood assays. Finally, 5 (50 mg/kg) and 6 (275 mg/kg) displayed analgesic activities comparable to paracetamol (200 mg/kg) in the mouse formalin test.

Dopamides, vanillylamides, ethanolamides, and arachidonic acid amides of anti-inflammatory and analgesic drug substances as TRPV1 ligands.

Drug substances can be acylated metabolically to give derivatives with specific and strong molecular effects. We generated potentially naturally occurring acid amides of several anti-inflammatory and analgesic drugs. In the amides, the drug moieties served either as amine or acid components. All compounds were evaluated for activity toward transient receptor potential vanilloid subfamily member 1 (TRPV1) in a cell-based Ca2+ influx assay; TRPV1 is a key receptor in the pain pathway and a promising target for analgesic drugs. We found that dopamine amides of fenamic acids have TRPV1 agonist activity in the nanomolar range, and that the arachidonoyl amide of a dipyrone metabolite has TRPV1 antagonist activity. Flufenamic acid dopamide, the most potent TRPV1 agonist reported herein, retains the cyclooxygenase (COX) inhibition properties of the parent compound flufenamic acid. Thus it acts on two different major players in the pain processing machinery. The compounds could be further keys to understanding the mechanism of action of fenamates and dipyrone at the molecular level. The fenamic acid dopamine amides qualify as new lead structures for drug development.