Enzyme inhibitor
This (–)-(R)-phosphonic acid (FW = 249.63 g/mol; CAS 108351-35-5), systematically named as 3-amino-2-(4-chlorophenyl)propanephosphonic acid, is a GABABγ-aminobutyric acid receptor antagonist. Although synaptic action of GABA is mediated by bicuculline-sensitive GABAA receptors that selectively increase chloride conductance, GABA has a presynaptic inhibitory action that is bicuculline-insensitive and is mimicked by baclofen. This distinctive behavior defines the GABAB receptor, allowing one to distinguish them from classic bicuculline-sensitive GABAAreceptors. In hippocampal slices, phaclofen (baclofen’s phosphonate derivative) is a remarkably selective antagonist of both the postsynaptic action of baclofen and GABA’s bicuculline-resistant action. Phaclofen selectively abolishes the slow inhibitory postsynaptic potential in pyramidal cells. It is ineffective in antagonizing competitively the synapticallymediated Late Hyperpolarizing Response (LHP) recorded from the same or similar Dorsolateral Septal Nucleus (DLSN) neurons, from which baclofen responses were recorded. Such findings support the usefulness of phaclofen as a competitive antagonist of baclofen, and suggest that when larger stimulus intensities are applied, the LHP in the rat DLS may be mediated by a transmitter in addition to GABA. Moreover,-(R)- phaclofen inhibits the binding of [3H]-(R)-baclofen to GABAB receptor sites on rat cerebellar membranes (IC50 = 76 μM), whereas (+)-(S)-phaclofen is inactive (IC50 > 1000 μM).
