Homotaurine: a GABA_B antagonist in guinea‐pig ileum

Abstract

Homotaurine (3‐aminopropane sulphonic acid) did not inhibit the twitch response in guinea‐pig ileum longitudinal muscle whilst γ‐aminobutyric acid (GABA) and (−)‐baclofen evoked dose‐dependent inhibitions. The inhibitory effects of GABA and (−)‐baclofen were prevented in the presence of homotaurine 2 × 10−4 and 10−3 M. The log dose‐effect curves of GABA and (−)‐baclofen were shifted in a parallel manner compatible with competitive antagonism. The pA2 of homotaurine with GABA (4.22 ± 0.05) and (−)‐baclofen (4.26 ± 0.1) were the same. Homotaurine did not antagonize the inhibitory effects of morphine (ED50 4 × 10−7 M), noradrenaline (ED50 10−6 M) or ATP (ED50 1.5 × 10−5 M). The inferior homologue of homotaurine, taurine 10−3 M, did not modify the inhibitory effects of GABA and (−)‐baclofen. Picrotoxin 5 × 10−5 M antagonized GABAA receptor‐mediated contraction but did not affect GABAB receptor‐mediated inhibition. At the same concentration the drug did not influence the antagonistic action of homotaurine, thus showing no GABAA receptor‐mediated interference. It may be concluded that homotaurine is a competitive antagonist of GABAB mediated effects in the guinea‐pig ileum.

Agonists, antagonists and modulators of excitatory amino acid receptors in the guinea‐pig myenteric plexus

“…Since tetrodotoxin (3 x 10-7M) and hyoscine (10-7M) completely prevented L-Glu-induced contraction of the preparation, it appears that cholinergic neurones of the myenteric plexus are necessary for L-Glu-induced contractions of the ileum. It has previously been shown that GABAA-and GABAB-receptors are directly present on the cholinergic neurones of the myenteric plexus (Giotti et al, 1983;Cherubini & North, 1984). The possibility therefore exists that L-Glu receptors are also located on the cholinergic neurones.…”

“…The longitudinal muscle of their ilea with the myenteric plexus attached was prepared according to Paton & Zar (1968) with minor modifications (Giotti et al, 1983). Strips, about 3cm in length, weighing approximately 20mg, were prepared from the terminal portion of the ileum and placed in a modified Krebs solution of the following composition (mM): NaCI 135, CaCl2 2.4, KH2PO4 1.3, NaHCO3 16.3 and glucose 7.7.…”

“…The guinea-pig ileum-myenteric plexus preparation in vitro has been extremely useful in the pharmacological characterization of receptors for neurotransmitters with agonists and antagonists (Ash & Schild, 1966;Rang, 1966;Gyang & Kosterlitz, 1966;Cook, 1971;Black et al, 1972;Couture et al, 1979;Giotti et al, 1983). This knowledge prompted us to investigate whether or not the guinea-pig myenteric plexus contains excitatory amino acid receptors.…”

Exploring the other side of biologically relevant chemical space: Insights into carboxylic, sulfonic and phosphonic acid bioisosteric relationships

“…Results pinpointed that while phosphonate (3) and sulfonate (2) moieties interacted well with the binding site of the enzyme, the carboxylic group (1) did not yield a strong interaction. Phosponate and sulfonate were exploited as carboxylate mimics of GABAergic agonists, such as g-amino butyric acid (4, GABA) and baclofen (7) [23][24][25][26]. Strikingly, these replacements shifted the pharmacological profiles of the resulting compounds to GABAergic antagonists (5,6,8,9).…”

Synthesis and biological evaluation of GABA derivatives able to cross the blood–Brain barrier in rats

“…maximal inhibition=49 AE 8%; Àlog IC 50 =5.65 AE 0.14), as previously reported. 26 This effect on GABA B receptors subtypes was competitively antagonized by the selective GABA B blocker CGP-52432 (pK B =6.56 AE 0.10) and not competitively by compound 1 pD 0 2 ¼ 5:59 AE 0:16. Compounds 2 and 2a were completely ineffective in this test at concentrations up to 100 mM.…”