Synthesis and structure-activity relationships of a series of pyrrole cannabinoid receptor agonists.
We designed and synthesized a series of pyrrole derivatives with the aim of investigating the structure-activity relationship (SAR) for the binding of non-classical agonists to CB(1) and CB(2) cannabinoid receptors. Superposition of two pyrrole-containing cannabinoid agonists, JWH-007 and JWH-161, allowed us to identify positions 1, 3 and 4 of the pyrrole nucleus as amenable to additional investigation. We prepared the 1-alkyl-2,5-dimethyl-3,4-substituted pyrroles 10a-e, 11a-d, 17, 21, 25 and the tetrahydroindole 15, and evaluated their ability to bind to and activate cannabinoid receptors. Noteworthy in this set of compounds are the 4-bromopyrrole 11a, which has an affinity for CB(1) and CB(2) receptors comparable to that of well-characterized heterocyclic cannabimimetics such as Win-55,212-2; the amide 25, which, although possessing a moderate affinity for cannabinoid receptors, demonstrates that the 3-naphthoyl group, commonly present in indole and pyrrole cannabimimetics, can be substituted by alternative moieties; and compounds 10d, 11d, showing CB(1) partial agonist properties.
Tarzia
Giorgio
G
Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Urbino Carlo Bo, Piazza del Rinascimento 6, I-61029 Urbino, Italy. gat@uniurb.it
Duranti
Andrea
A
Tontini
Andrea
A
Spadoni
Gilberto
G
Mor
Marco
M
Rivara
Silvia
S
Vincenzo Plazzi
Pier
P
Kathuria
Satish
S
Piomelli
Daniele
D
D000818:Animals; D063386:Cannabinoid Receptor Agonists; D002462:Cell Membrane / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D011485:Protein Binding; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists; D013329:Structure-Activity Relationship
D063386:Cannabinoid Receptor Agonists; D007211:Indoles; D008024:Ligands; D011758:Pyrroles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011994:Recombinant Proteins