Piperidine-4-sulfonic acid

Pharmaceutical compound From Wikipedia, the free encyclopedia

Piperidine-4-sulfonic acid (P4S) is a synthetic GABA_A receptor agonist and a cyclized analogue of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).^[1]^[2]^[3]

Other namesPiperidine-4-sulphonic acid; P4S; PSA

Drug classGABA_A receptor partial agonist; GABA_A-ρ receptor antagonist

ATC code

None

CAS Number

72450-62-5

Quick facts Clinical data, Other names ...

Piperidine-4-sulfonic acid
Clinical data

Other names	Piperidine-4-sulphonic acid; P4S; PSA
Drug class	GABA_A receptor partial agonist; GABA_A-ρ receptor antagonist
ATC code	None
Identifiers
IUPAC name piperidine-4-sulfonic acid
CAS Number	72450-62-5
PubChem CID	4838
IUPHAR/BPS	4287
ChemSpider	4672
UNII	2M8K8ZJJ5U
ChEMBL	ChEMBL34155
CompTox Dashboard (EPA)	DTXSID70222752
Chemical and physical data
Formula	C₅H₁₁NO₃S
Molar mass	165.21 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES C1CNCCC1S(=O)(=O)O
InChI InChI=1S/C5H11NO3S/c7-10(8,9)5-1-3-6-4-2-5/h5-6H,1-4H2,(H,7,8,9) Key:UGBJGGRINDTHIH-UHFFFAOYSA-N

Pharmacology

The drug is a potent and selective GABA_A receptor partial agonist.^[4]^[2] It shows functional selectivity at GABA_A receptors of different α subunit compositions, with high activational efficacy at GABA_A receptors containing α₂, α₃, and α₅ subunits (E_maxTooltip maximal efficacy = 75–96%) and low efficacy at GABA_A receptors containing α₁, α₄, and α₆ subunits (E_max = 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 GABA_A receptor agonists like isoguvacine and gaboxadol (THIP), which show broadly higher activational efficacies at GABA_A receptors of different subunit compositions.^[1]^[5] In addition to its GABA_A receptor partial agonism, P4S is described as a moderately potent GABA_A-ρ receptor antagonist, a property that it shares with gaboxadol.^[6]^[7] Unlike certain related compounds like muscimol, P4S is not a GABA reuptake inhibitor.^[2]

P4S is a highly charged zwitterion.^[8] In contrast to other related GABA_A receptor agonists like muscimol and gaboxadol, P4S is unable to cross the blood–brain barrier and hence is peripherally selective.^[9]^[8] As a result of this, animal behavioral studies with this compound have not been possible.^[9]^[8]

Discovery

P4S was first described in the scientific literature by Povl Krogsgaard-Larsen and colleagues by 1979.^[10]^[2] Along with gaboxadol, it was one of the first selective GABA_A receptor agonists to be identified.^[3]^[1]

References

[1]
Frølund B, Ebert B, Kristiansen U, Liljefors T, Krogsgaard-Larsen P (August 2002). "GABA(A) receptor ligands and their therapeutic potentials". Current Topics in Medicinal Chemistry. 2 (8): 817–832. doi:10.2174/1568026023393525. PMID 12171573. 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 [...]
[2]
Krogsgaard-Larsen P, Falch E, Schousboe A, Curtis DR, Lodge D (March 1980). "Piperidine-4-sulphonic acid, a new specific GABA agonist". Journal of Neurochemistry. 34 (3): 756–759. doi:10.1111/j.1471-4159.1980.tb11211.x. PMID 7354350.
[3]
Krogsgaard-Larsen P, Frølund B, Liljefors T (2002). "Specific GABA(A) agonists and partial agonists". Chemical Record. 2 (6): 419–430. doi:10.1002/tcr.10040. PMID 12469353. 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
[4]
Krogsgaard-Larsen P, Frølund B, Jørgensen FS, Schousboe A (August 1994). "GABAA receptor agonists, partial agonists, and antagonists. Design and therapeutic prospects". Journal of Medicinal Chemistry. 37 (16): 2489–2505. doi:10.1021/jm00042a001. PMID 8057295.
[5]
Ebert B, Mortensen M, Thompson SA, Kehler J, Wafford KA, Krogsgaard-Larsen P (June 2001). "Bioisosteric determinants for subtype selectivity of ligands for heteromeric GABA(A) receptors". Bioorganic & Medicinal Chemistry Letters. 11 (12): 1573–1577. doi:10.1016/s0960-894x(01)00184-6. PMID 11412984.
[6]
Chebib M, Johnston GA (April 2000). "GABA-Activated ligand gated ion channels: medicinal chemistry and molecular biology". Journal of Medicinal Chemistry. 43 (8): 1427–1447. doi:10.1021/jm9904349. PMID 10780899.
[7]
Bormann J, Feigenspan A (December 1995). "GABAC receptors". Trends in Neurosciences. 18 (12): 515–519. doi:10.1016/0166-2236(95)98370-e. PMID 8638289.
[8]
Wafford KA, Ebert B (February 2006). "Gaboxadol--a new awakening in sleep". Current Opinion in Pharmacology. 6 (1): 30–36. doi:10.1016/j.coph.2005.10.004. PMID 16368265. 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].
[9]
Krogsgaard-Larsen P (December 1981). "gamma-Aminobutyric acid agonists, antagonists, and uptake inhibitors. Design and therapeutic aspects". Journal of Medicinal Chemistry. 24 (12): 1377–1383. doi:10.1021/jm00144a001. PMID 6118436. 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.
[10]
Braestrup C, Nielsen M, Krogsgaard-Larsen P, Falch E (July 1979). "Partial agonists for brain GABA/benzodiazepine receptor complex". Nature. 280 (5720): 331–333. Bibcode:1979Natur.280..331B. doi:10.1038/280331a0. PMID 460407.

Piperidine-4-sulfonic acid

Pharmacology

Discovery

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