Synthesis and pharmacological characterisation of 2,4-dicarboxy-pyrroles as selective non-competitive mGluR1 antagonists.
Metabotropic glutamate receptors (mGluRs) are an unusual family of G-protein coupled receptor (GPCR), and are characterised by a large extracellular N-terminal domain that contains the glutamate binding site. We have identified a new class of non-competitive metabotropic glutamate receptor 1 (mGluR1) antagonists, 2,4-dicarboxy-pyrroles which are endowed with nanomolar potency. They interact within the 7 transmembrane (7TM) domain of the receptor and show antinociceptive properties when tested in a number of different animal models.
Micheli
Fabrizio
F
GlaxoSmithkline Medicine Research Centre, Via Fleming, 4-37135 Verona, Italy. fm20244@gsk.com
Fabio
Romano Di
RD
Cavanni
Paolo
P
Rimland
Joseph M
JM
Capelli
Anna Maria
AM
Chiamulera
Cristiano
C
Corsi
Mauro
M
Corti
Corrado
C
Donati
Daniele
D
Feriani
Aldo
A
Ferraguti
Francesco
F
Maffeis
Micaela
M
Missio
Andrea
A
Ratti
Emiliangelo
E
Paio
Alfredo
A
Pachera
Roberta
R
Quartaroli
Mauro
M
Reggiani
Angelo
A
Sabbatini
Fabio Maria
FM
Trist
David G
DG
Ugolini
Annarosa
A
Vitulli
Giovanni
G
D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D004594:Electrophysiology / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D010147:Pain Measurement / Q000187:drug effects; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D018712:Analgesics, Non-Narcotic; D011758:Pyrroles; D018094:Receptors, Metabotropic Glutamate; D011993:Recombinant Fusion Proteins; C104077:metabotropic glutamate receptor type 1