Dihydromuscimol, Thiomuscimol and Related Heterocyclic Compounds as Gaba Analogues

Abstract

A series of heterocyclic GABA analogues related to muscimol (5‐aminomethyl‐3‐isoxazolol) were tested as depressants of the firing of GABA sensitive neurones on the cat spinal cord, and as inhibitors of the sodium‐independent binding of GABA to rat brain membranes. Furthermore, the compounds were examined as inhibitors of GABA uptake into rat brain slices and as inhibitors of the activities of the GABA‐metabolizing enzymes L‐glutamate 1‐carboxylyase and GABA:2‐oxoglutarate aminotransferase.Dihydromuscimol [(RS)‐4,5‐dihydromuscimol] and thiomuscimol (5‐aminomethyl‐3‐isothiazolol) were approximately equipotent to muscimol as bicuculline‐sensitive depressants of neuronal firing and as inhibitors of GABA binding. The structurally related compounds isomuscimol (3‐aminomethyl‐5‐isoxa‐zolol) and azamuscimol (5‐aminomethyl‐3‐pyrazolol) were much weaker than muscimol as GABA agonists. The affinity of the compounds for GABA receptor sites in vitro is in agreement with their relative potency as GABA receptor agonists in vivo. The rat brain synaptic membranes used for the GABA receptor binding studies were prepared by two procedures, which were shown to have a pronounced influence on the observed potency of the inhibitors of GABA binding.The compounds were weak or inactive as inhibitors of the uptake of GABA into rat brain slices and of the activity of GABA: 2‐oxoglutarate aminotransferase in vitro. Azamuscimol and 2‐methylaza‐muscimol were moderately potent inhibitors.of the activity of L‐glutamate 1‐carboxylyase in vitro. This inhibition by azamuscimol was timedependent following pseudo‐first‐order kinetics, consistent with azamuscimol acting as a catalytic inhibitor.The structure of the heterocyclic rings of these zwitterionic compounds is a factor of critical importance for interaction with GABA receptors. The present structure‐activity analysis demonstrates that heterocyclic GABA analogues having a high degree of delocalization of the negative charges have low affinity for the GABA receptors.

Differences between GABA Receptor Binding to Membranes from Cerebellum during Postnatal Development and from Cultured Cerebellar Granule Cells

“…Piperidines substituted with a carboxyl group in the 3-position were ineffective whereas a carboxyl group in the 4-position made the compounds potent displacers of GABA binding [18]. It was, however, sur prising that THIP was found to be more po tent than isoguvacine in displacing GABA binding, since the opposite has been reported both for effects on GABA binding to rat brain membranes [21,22] and on the firing rate of spinal interneurons [23]. Also the new GABA analogue, homo-/3-proline, was found to be more potent as an inhibitor of GABA binding to cultured granule cells than of GABA binding to rat brain membranes [25].…”

Mapping Functional Alterations in the CNS With [14C]Deoxyglucose

“…Although the actions of muscimol and THIP are similar in many respects, a number of important differences do exist in their pharmacological profiles (Krogsgaard-Larsen et at., 1979a). Both muscimol and THIP depress the firing of GABA-sensitive neurons of the spinal cord, each inhibit the binding of [3H]GABA to brain tissue and, as both agents pass across the blood-brain barrier, each has marked central effects following systemic administration (Krogsgaard-Larsen et at., 1979a,b).…”

Isothiouronium compounds as γ‐aminobutyric acid agonists

“…It is well known that introduction of n-electrons into the carbon chain of a GABA analogue, although not essential for high potency (Krogsgaard-Larsen et al, 1979), is consistent with retained activity as in trans-4-aminocrotonic acid or muscimol (Krogsgaard-Larsen & Falch, 1981), and the potent compounds can be considered as containing trans substituted carbon-carbon double bonds. It was not surprising that conformational restriction of the active compound 2, by introduction of a double bond, should generate two geometric isomers, one of which is more active and the other which is less active than 2.…”