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 monoph enylester (RS)-alpha-methylserine-O-phosphate monophenylphosphoryl est er (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 motoneuron es, mediated via metabotropic glutamate receptors (mGluRs). MSOP was s hown to be a selective antagonist for the L-AP4-sensitive presynaptic mGluR, displaying an apparent K-D of 51 mu M, compared to >700 mu M fo r the (1S,3S)-ACPD-sensitive presynaptic mGluR. In contrast, MSOPPE di splayed antagonist activity at both presynaptic mGluRs, with a three t imes greater selectivity for the (1S,3S)-ACPD-sensitive receptor over the L-AP4-sensitive mGluR (apparent K-D values 73 mu M and 221 mu M, r espectively). Therefore, on addition of an alpha-methyl group to the m GluR agonist serine-O-phosphate, we have developed an mGluR antagonist which is selective for the presynaptic L-AP4-sensitive receptor. In c ontrast, monoesterification of MSOP to give the monophenylphosphoryl e ster (MSOPPE), confers a degree of selectivity for the (1S,3S)-ACPD- o ver the L-AP4-sensitive presynaptic mGluR. Neither MSOP nor MSOPPE had any activity on either postsynaptic mGluRs or ionotropic receptors. C opyright (C) 1996 Elsevier Science Ltd.