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| Other names | Piperidine-4-sulphonic acid; P4S; PSA |
| Drug class | GABAA receptorpartial agonist;GABAA-ρ receptorantagonist |
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| Formula | C5H11NO3S |
| Molar mass | 165.21 g·mol−1 |
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Piperidine-4-sulfonic acid (P4S) is asyntheticGABAA receptoragonist and acyclizedanalogue of theinhibitoryneurotransmitterγ-aminobutyric acid (GABA).[1][2][3]
The drug is apotent andselective GABAA receptorpartial agonist.[4][2] It showsfunctional selectivity at GABAA receptors of different αsubunit compositions, with highactivationalefficacy at GABAA receptors containingα2,α3, andα5 subunits (EmaxTooltip maximal efficacy = 75–96%) and low efficacy at GABAA receptors containingα1,α4, andα6 subunits (Emax = 7.2–21%).[1][5] As such, it is said to activate the former receptors but to essentially block the latter receptors.[1][5] This is in contrast to other GABAA receptor agonists likeisoguvacine andgaboxadol (THIP), which show broadly higher activational efficacies at GABAA receptors of different subunit compositions.[1][5] In addition to its GABAA receptor partial agonism, P4S is described as a moderately potentGABAA-ρ receptorantagonist, a property that it shares with gaboxadol.[6][7] Unlike certain related compounds likemuscimol, P4S is not aGABA reuptake inhibitor.[2]
P4S is a highly chargedzwitterion.[8] In contrast to other related GABAA receptor agonists like muscimol and gaboxadol, P4S is unable to cross theblood–brain barrier and hence isperipherally selective.[9][8] As a result of this, animal behavioral studies with this compound have not been possible.[9][8]
P4S was first described in thescientific literature byPovl Krogsgaard-Larsen and colleagues by 1979.[10][2] Along with gaboxadol, it was one of the first selective GABAA receptor agonists to be identified.[3][1]
The pharmacological characterization of the GABAA receptors was accelerated by the development of specific GABAA agonists such as isoguvacine, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) and piperidin-4- sulphonic acid (P4S) [11, 12]. [...] Whereas P4S effectively activates a2 and a5 containing receptors it essentially blocks the a4 and a6 containing receptors. [...] As observed for THIP, the heterocyclic GABA isosteres IAA and P4S show the characteristics of a partial GABAA agonist [61, 63]. As described for the analogues of isoguvacine, it has been shown, using GABAA abg receptors cloned in oocytes, that the relative efficacy as well as the potency for these compounds is highly dependent on the receptor subunit combination (Table 1) [57]. [...] Table 1. Agonist Activity and Antagonist Potencies as Function of GABAA Receptor Subunit Composition [...]
The subsequent design of isoguvacine, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP)19 (Fig. 1) and piperidine-4-sulphonic acid (P4S)20 as specific GABA agonists further stimulated studies into the pharmacology of the GABA receptors. [...] It is interesting to note that even though isoguvacine is an order of magnitude more potent than the corresponding saturated cyclic amino acid isonipecotic acid as a GABAA agonist,19 the unsaturated analog of P4S, DH-P4S, is an order of magnitude weaker than P4S as an agonist at the GABAA receptors (Fig. 6).20 The sulphonic acid analog of nipecotic acid, P3S, does not significantly affect GABA uptake,47 whereas the corresponding phosphinic acid, piperidinyl-3-phosphinic acid (Fig. 6), is a GABA uptake inhibitor, although somewhat weaker than nipecotic acid.48
Early studies demonstrated that the highly charged zwitterions isoguvacine and P4S were unable to enter the CNS or exert any pharmacological activity, whereas muscimol and (to an even larger extent) gaboxadol produced observable changes in behaviour after systemic application [25].
Unfortunately, comparative behavioral studies of GABA, muscimol, isoguvacine, THIP, and P4S are not possible. Only THIP and muscimol are capable of penetrating the blood-brain barrier (BBB), and while THIP is stable in vivo,56 muscimol is very rapidly decomposed after peripheral administration.57 [...] Activation of the central and peripheral GABA receptors stimulates and inhibits, respectively, prolactin release,92 suggesting that GABA agonists like P4S and isoguvacine, which do not pass the BBB, have therapeutic interest in this clinical situation.
