alpha-Methyl derivatives of serine-O-phosphate as novel, selective competitive metabotropic glutamate receptor antagonists.
The antagonist selectivity and potency of two novel serine-O-phosphate derivatives (RS)-alpha-methylserine-O-phosphate (MSOP) and the monophenylester (RS)-alpha-methylserine-O-phosphate monophenyl-phosphoryl ester (MSOPPE) was investigated against L-2-amino-4-phosphonobutyrate (L-AP4)- and (1S,3S)-1-aminocyclopentane-1, 3-dicarboxylate (ACPD)-induced depressions of the monosynaptic excitation of neonatal rat motoneurones, mediated via metabotropic glutamate receptors (mGLuRs). MSOP was shown to be a selective antagonist for the L-AP4-sensitive presynaptic mGluR, displaying an apparent KD of 51 microM, compared to > 700 microM for the (1S,3S)-ACPD-sensitive presynaptic mGluR. In contrast, MSOPPE displayed antagonist activity at both presynaptic mGluR, with a three times greater selectivity for the (1S,3S)-ACPD-sensitive receptor over the L-AP4-sensitive mGluR (apparent KD values 73 microM and 221 microM, respectively). Therefore, on addition of an alpha-methyl group to the mGluR agonist serine-O-phosphate, we have developed an mGluR antagonist which is selective for the presynaptic L-AP4-sensitive receptor. In contrast, monoesterification of MSOP to give the monophenylphosphoryl ester (MSOPPE), confers a degree of selectivity for the (1S,3S)-ACPD-over the L-AP4-sensitive presynaptic mGluR. Neither MSOP nor MSOPPE had any activity on either postsynaptic mGLuRs or ionotropic receptors.
Department of Pharmacology, School of Medical Sciences, Bristol, UK.
N K
NK
Thomas
D E
DE
Jane
H W
HW
Tse
J C
JC
Watkins
D000818:Animals; D004305:Dose-Response Relationship, Drug; D009046:Motor Neurons / Q000187:drug effects*; D016202:N-Methylaspartate / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D012694:Serine / Q000031:analogs & derivatives*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D018094:Receptors, Metabotropic Glutamate; D012694:Serine; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid