BML-190BML-190 (indomethacin morpholinylamide)

Formula

C₂₃H₂₃ClN₂O₄

Molar mass

426.13 g·mol⁻¹

CAS

2854-32-2

PubChem CID

2415

Origin

A wholly synthetic compound, derived from an existing medicine. It is produced as a pharmacology reagent and has not been the subject of clinical development of its own.

InChIKey

BJSDNVVWJYDOLK-UHFFFAOYSA-N

Editorial estimate, not clinical.

BML-190 illustrates how a minimal chemical modification can redirect a molecule towards an entirely different target. Indomethacin is a non-steroidal anti-inflammatory known since the 1960s, whose activity rests on the inhibition of cyclooxygenases by its carboxylic acid function. Turning that acid into a morpholine amide removes that activity and brings out an affinity for the cannabinoid CB2 receptor. New and Wong clarified in 2003 the nature of that interaction, a question not resolved by the measurement of an affinity alone. A ligand may activate a receptor, block it without more, or reduce the activity the receptor exerts spontaneously in the absence of any agonist; that last behaviour, inverse agonism, is revealed only in systems where such constitutive activity is measurable. The authors worked on cells expressing the human CB2 receptor abundantly and observed that the compound potentiates the accumulation of cyclic AMP induced by forskolin, the exact opposite of the effect of an agonist, and that it lowers the basal production of inositol phosphates when the receptor is coupled to a chimeric G protein. The compound therefore acts on two families of signalling pathways. Its reach is that of a tool: it makes it possible to demonstrate that the CB2 receptor possesses spontaneous activity and to quantify it. Its metabolism has moreover been characterised on rat liver microsomes, where at least fifteen products were identified, which makes it one of the few laboratory CB2 ligands whose metabolic fate has been described.

An entirely chemical route, described here by class only. The molecule derives from indomethacin by transformation of its carboxylic acid function into a morpholine amide. The rest of the skeleton is preserved: a methoxylated and methylated indole core, acylated on its nitrogen by a chlorobenzoyl. That modification of a single function tips the molecule from the profile of a cyclooxygenase inhibitor towards that of a CB2 receptor ligand.

Sources: EUR-Lex, UNODC, CND, ANSM, IUPHAR/BPS, ChEBI, EUDA. Our method.

Class

ECS modulator (research)

Origin

A wholly synthetic compound, derived from an existing medicine. It is produced as a pharmacology reagent and has not been the subject of clinical development of its own.

Status

Unscheduled

1. 1.New et Wong 2003 : le BML-190 et l'AM251 agissent en agonistes inverses au récepteur CB2 humain, signalisation par l'AMP cyclique et les inositol phosphatesPMID 12586356
2. 2.Zhang et coll. 2010 : métabolisme in vitro de l'indométacine morpholinylamide sur microsomes hépatiques de ratPMID 20542112