Chemistry:Piperidine-4-sulfonic acid

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Piperidine-4-sulfonic acid
File:Piperidine 4-sulfonic acid.svg
Clinical data
Other namesPiperidine-4-sulphonic acid; P4S; PSA
Drug classGABAA receptor partial agonist; GABAA-ρ receptor antagonist
ATC code
  • None
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC5H11NO3S
Molar mass165.21 g·mol−1
3D model (JSmol)

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

Pharmacology

The drug is a potent and selective GABAA receptor partial agonist.[4][2] It shows functional selectivity at GABAA receptors of different α subunit compositions, with high activational efficacy at GABAA receptors containing α2, α3, and α5 subunits (Emax = 75–96%) and low efficacy at GABAA receptors containing α1, α4, and α6 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 like isoguvacine and gaboxadol (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 potent GABAA-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 GABAA 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 GABAA receptor agonists to be identified.[3][1]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "GABA(A) receptor ligands and their therapeutic potentials". Current Topics in Medicinal Chemistry 2 (8): 817–832. August 2002. 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. ↑ 2.0 2.1 2.2 2.3 "Piperidine-4-sulphonic acid, a new specific GABA agonist". Journal of Neurochemistry 34 (3): 756–759. March 1980. doi:10.1111/j.1471-4159.1980.tb11211.x. PMID 7354350. 
  3. ↑ 3.0 3.1 "Specific GABA(A) agonists and partial agonists". Chemical Record 2 (6): 419–430. 2002. 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. ↑ "GABAA receptor agonists, partial agonists, and antagonists. Design and therapeutic prospects". Journal of Medicinal Chemistry 37 (16): 2489–2505. August 1994. doi:10.1021/jm00042a001. PMID 8057295. 
  5. ↑ 5.0 5.1 5.2 "Bioisosteric determinants for subtype selectivity of ligands for heteromeric GABA(A) receptors". Bioorganic & Medicinal Chemistry Letters 11 (12): 1573–1577. June 2001. doi:10.1016/s0960-894x(01)00184-6. PMID 11412984. 
  6. ↑ "GABA-Activated ligand gated ion channels: medicinal chemistry and molecular biology". Journal of Medicinal Chemistry 43 (8): 1427–1447. April 2000. doi:10.1021/jm9904349. PMID 10780899. 
  7. ↑ "GABAC receptors". Trends in Neurosciences 18 (12): 515–519. December 1995. doi:10.1016/0166-2236(95)98370-e. PMID 8638289. 
  8. ↑ 8.0 8.1 8.2 "Gaboxadol--a new awakening in sleep". Current Opinion in Pharmacology 6 (1): 30–36. February 2006. 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. ↑ 9.0 9.1 "gamma-Aminobutyric acid agonists, antagonists, and uptake inhibitors. Design and therapeutic aspects". Journal of Medicinal Chemistry 24 (12): 1377–1383. December 1981. 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. ↑ "Partial agonists for brain GABA/benzodiazepine receptor complex". Nature 280 (5720): 331–333. July 1979. doi:10.1038/280331a0. PMID 460407. Bibcode: 1979Natur.280..331B. 

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See also
Receptor/signaling modulators
GABAA receptor positive modulators
GABA metabolism/transport modulators

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