Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson's disease treatment.
Parkinson's disease (PD) is a debilitating movement disorder that afflicts >1 million people in North America. Current treatments focused on dopamine-replacement strategies ultimately fail in most patients because of loss of efficacy and severe adverse effects that worsen as the disease progresses. The recent success of surgical approaches suggests that a pharmacological intervention that bypasses the dopamine system and restores balance in the basal ganglia motor circuit may provide an effective treatment strategy. We previously identified the metabotropic glutamate receptor 4 (mGluR4) as a potential drug target and predicted that selective activation of mGluR4 could provide palliative benefit in PD. We now report that N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) is a selective allosteric potentiator of mGluR4. This compound selectively potentiated agonist-induced mGluR4 activity in cultured cells expressing this receptor and did not itself act as an agonist. Furthermore, PHCCC potentiated the effect of l-(+)-2-amino-4-phosphonobutyric acid in inhibiting transmission at the striatopallidal synapse. Modulation of the striatopallidal synapse has been proposed as a potential therapeutic target for PD, in that it may restore balance in the basal ganglia motor circuit. Consistent with this, PHCCC produced a marked reversal of reserpine-induced akinesia in rats. The closely related analogue 7-(hydroxylimino)cyclopropachromen-1a-carboxamide ethyl ester, which does not potentiate mGluR4, had no effect in this model. These results are evidence for in vivo behavioral effects of an allosteric potentiator of mGluRs and suggest that potentiation of mGluR4 may be a useful therapeutic approach to the treatment of PD.
Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA. michael_marino@merck.com
Michael J
MJ
Marino
David L
DL
Williams
Julie A
JA
O'Brien
Ornella
O
Valenti
Terrence P
TP
McDonald
Michelle K
MK
Clements
Ruiping
R
Wang
Anthony G
AG
DiLella
J Fred
JF
Hess
Gene G
GG
Kinney
P Jeffrey
PJ
Conn
D000495:Allosteric Site; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004594:Electrophysiology; D004952:Esters / Q000494:pharmacology; D006801:Humans; D008297:Male; D008954:Models, Biological; D008956:Models, Chemical; D010300:Parkinson Disease / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry* / Q000378:metabolism; D013569:Synapses; D013997:Time Factors
C117789:7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester; D001578:Benzopyrans; D002867:Chromones; D004952:Esters; C442478:N-phenyl-7-(hydroxyimino)cyclopropa(b)chromen-1a-carboxamide; D018094:Receptors, Metabotropic Glutamate; D004298:Dopamine; C108823:metabotropic glutamate receptor 4