Chemistry of GABAB Modulators

Synthesis and Pharmacological Evaluation of Novel γ-Aminobutyric Acid Type B (GABAB) Receptor Agonists as Gastroesophageal Reflux Inhibitors

“…Despite the fact that the molecules contain a P−H bond, it is notable that the novel 3-aminopropylphosphinic acid derivatives have metabolic properties making them useful as drugs even when given perorally. This finding was unexpected because contradictory results of the compound class have previously been reported in the literature. , The discovery is exemplified by the fact that the bioavailability of compound ( S )- 3 is 88% in dog and 78% in rat.…”

“…We decided to explore derivatives of 3-aminopropylphosphinic acid ( 1 , CGP27492), since this compound has been demonstrated to be a potent and selective GABA B agonist . As compound 1 has been described in the literature as being inactive in vivo (as a muscle relaxant), speculatively because of metabolic lability of the P−H bond, , we soon focused on derivatives of 3-aminopropyl(methyl)phosphinic acid ( 2 , SK&F97541) to avoid this metabolic liability . However, as it proved difficult to significantly improve the therapeutic window for derivatives of 2 , we eventually decided to re-evaluate the alleged metabolic lability of 1 and its P−H congeners.…”

“…However, as it proved difficult to significantly improve the therapeutic window for derivatives of 2 , we eventually decided to re-evaluate the alleged metabolic lability of 1 and its P−H congeners. Surprisingly, , we found that it was possible to design new P−H phosphinic acids that showed a high metabolic stability (see data for ( S )- 3 in Results and Discussion). Since 1 has been found to be inactive at CNS GABA B receptors after systemic administration, our hypothesis was that 3-aminopropylphosphinic acids may inhibit TLESR through a peripheral site of action without carrying the burden of CNS side effects.…”

Tonic Activation of Presynaptic GABAB Receptors in the Opener Neuromuscular Junction of Crayfish

“…Thus, in relation to the agents examined so far (GABA, baclofen, 3-APPA, phaclofen and 2-OH-saclofen), the pharmacology of the crustacean GABA B receptor closely resembles that of its mammalian counterpart. We did not attempt to use the more recent, potent agonists or antagonists for GABA B receptors, based on P-substituted phosphinic analogues of GABA (Froestl and Mickel 1997), because many of these have been found to have significant affinity for GABA C receptors, which crustacean GABA A receptors closely resemble (Johnston 1997).…”

Ligand-gated Ion Channels

“…(1.5 nM; Bittiger et al, 1992), [ 3 H]CGP62349 (0.9 nM, Keir et al, 1999), [ 125 I]CGP64213 (1 nM, Galvez et al, 2000), [ 125 I]CGP71872 (Ki = 0.5 nM, Belley et al, 1999) Potencies of agonists and antagonists listed in the table, quantified as IC50 values for the inhibition of [ 3 H]CGP27492 binding to rat cerebral cortex membranes, are from Froestl and Mickel (1997), Bowery et al (2002) andFroestl (2011). Radioligand KD values relate to binding to rat brain membranes.…”