Name: bis(2,5-dioxopyrrolidin-1-yl) 4,4'-disulfanediyldibutanoate
Brand: BOC Sciences
Rating: 5 (1 reviews)

Synonyms

1,1'-{Disulfanediylbis[(1-oxo-4,1-butanediyl)oxy]}di(2,5-pyrrolidinedione);

IUPAC Name

Canonical SMILES

C1CC(=O)N(C1=O)OC(=O)CCCSSCCCC(=O)ON2C(=O)CCC2=O

InChI

InChI=1S/C16H20N2O8S2/c19-11-5-6-12(20)17(11)25-15(23)3-1-9-27-28-10-2-4-16(24)26-18-13(21)7-8-14(18)22/h1-10H2

InChIKey

FCGMACUPMXOQJD-UHFFFAOYSA-N

Appearance

Soild powder

Shipping

Room temperature

Bis(2,5-dioxopyrrolidin-1-yl) 4,4’-disulfanediyldibutanoate, more commonly known as SPDP, serves as a versatile crosslinking reagent extensively utilized in biochemistry and molecular biology. Here are four key applications of SPDP, presented with a high degree of perplexity and burstiness:

Protein Crosslinking: The versatile nature of SPDP makes it a favored choice for crosslinking proteins, facilitating the study of intricate protein-protein interactions. By establishing stable connections between proteins, researchers can delve into the structural and functional repercussions of these interactions, unearthing crucial insights into the cellular mechanisms and pathways in which these proteins partake.

Antibody Conjugation: Widely acknowledged for its efficacy in antibody conjugation, SPDP plays a pivotal role in linking antibodies to diverse molecules, like enzymes or fluorophores, for diagnostic and therapeutic endeavors. The unique disulfide bond present in SPDP enables facile reduction and reformation, orchestrating the controlled assembly and disassembly of the conjugate. This technique holds immense significance in the development of targeted drug delivery systems and sensitive diagnostic assays.

Surface Modification: SPDP’s adaptability extends to surface modification, where it facilitates the introduction of functional groups onto surfaces, enabling the attachment of biological molecules onto various substrates. This capability proves invaluable in the fabrication of biosensors and biochips, where surface-bound proteins or nucleic acids are requisite for detection purposes. The use of SPDP in surface modifications elevates the stability and functionality of biosensing platforms, laying the groundwork for enhanced detection mechanisms.

Peptide Synthesis: In the realm of peptide synthesis, SPDP emerges as a key player, offering the ability to introduce thiol-reactive sites for subsequent functional modifications. This feature allows for the integration of additional chemical functionalities or the creation of cyclic peptides through disulfide bonds. Leveraging SPDP in peptide chemistry unlocks avenues for the synthesis of complex bioactive peptides with diverse applications spanning research and therapy.

1. Selective monoacylglycerol lipase inhibitors: antinociceptive versus cannabimimetic effects in mice

Aron H Lichtman, Mohammed Mustafa, Micah Niphakis, Rehab Abdullah, Benjamin F Cravatt, Jenny L Wilkerson, Bogna Ignatowska-Jankowska, Jenny L Wiley J Pharmacol Exp Ther . 2015 May;353(2):424-32. doi: 10.1124/jpet.114.222315.

The endogenous cannabinoid 2-arachidonoylglycerol (2-AG) plays an important role in a variety of physiologic processes, but its rapid breakdown by monoacylglycerol lipase (MAGL) results in short-lived actions. Initial MAGL inhibitors were limited by poor selectivity and low potency. In this study, we tested JZL184 [4-nitrophenyl 4-[bis(2H-1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate] and MJN110 [2,5-dioxopyrrolidin-1-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate], MAGL inhibitors that possess increased selectivity and potency, in mouse behavioral assays of neuropathic pain [chronic constriction injury (CCI) of the sciatic nerve], interoceptive cannabimimetic effects (drug-discrimination paradigm), and locomotor activity in an open field test. MJN110 (1.25 and 2.5 mg/kg) and JZL184 (16 and 40 mg/kg) significantly elevated 2-AG and decreased arachidonic acid but did not affect anandamide in whole brains. Both MAGL inhibitors significantly reduced CCI-induced mechanical allodynia with the following potencies [ED50 (95% confidence limit [CL]) values in mg/kg: MJN110 (0.43 [0.30-0.63]) > JZL184 (17.8 [11.6-27.4])] and also substituted for the potent cannabinoid receptor agonist CP55,940 [2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol] in the drug-discrimination paradigm [ED50 (95% CL) values in mg/kg: MJN110 (0.84 [0.69-1.02]) > JZL184 (24.9 [14.6-42.5])]; however, these compounds elicited differential effects on locomotor behavior. Similar to cannabinoid 1 (CB1) receptor agonists, JZL184 produced hypomotility, whereas MJN110 increased locomotor behavior and did not produce catalepsy or hypothermia. Although both drugs substituted for CP55,940 in the drug discrimination assay, MJN110 was more potent in reversing allodynia in the CCI model than in producing CP55,940-like effects. Overall, these results suggest that MAGL inhibition may alleviate neuropathic pain, while displaying limited cannabimimetic effects compared with direct CB1 receptor agonists.

2. Discriminative Stimulus Properties of the Endocannabinoid Catabolic Enzyme Inhibitor SA-57 in Mice

Aron H Lichtman, Robert A Owens, Mohammed Mustafa, Abdulmajeed Jali, Dana E Selley, Benjamin F Cravatt, Bogna Ignatowska-Jankowska, Jenny L Wiley, Micah J Niphakis, Patrick M Beardsley J Pharmacol Exp Ther . 2016 Aug;358(2):306-14. doi: 10.1124/jpet.115.229492.

Whereas the inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the respective major hydrolytic enzymes of N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), elicits no or partial substitution for Δ(9)-tetrahydrocannabinol (THC) in drug-discrimination procedures, combined inhibition of both enzymes fully substitutes for THC, as well as produces a constellation of cannabimimetic effects. The present study tested whether C57BL/6J mice would learn to discriminate the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) from vehicle in the drug-discrimination paradigm. In initial experiments, 10 mg/kg SA-57 fully substituted for CP55,940 ((-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol), a high-efficacy CB1 receptor agonist in C57BL/6J mice and for AEA in FAAH (-/-) mice. Most (i.e., 23 of 24) subjects achieved criteria for discriminating SA-57 (10 mg/kg) from vehicle within 40 sessions, with full generalization occurring 1 to 2 hours postinjection. CP55,940, the dual FAAH-MAGL inhibitor JZL195 (4- nitrophenyl 4- (3- phenoxybenzyl)piperazine- 1- carboxylate), and the MAGL inhibitors MJN110 (2,5-dioxopyrrolidin-1-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate) and JZL184 (4-[Bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) fully substituted for SA-57. Although the FAAH inhibitors PF-3845 ((N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) and URB597 (cyclohexylcarbamic acid 3'-(aminocarbonyl)-[1,1'-biphenyl]-3-yl ester) did not substitute for SA-57, PF-3845 produced a 2-fold leftward shift in the MJN110 substitution dose-response curve. In addition, the CB1 receptor antagonist rimonabant blocked the generalization of SA-57, as well as substitution of CP55,940, JZL195, MJN110, and JZL184. These findings suggest that MAGL inhibition plays a major role in the CB1 receptor-mediated SA-57 training dose, which is further augmented by FAAH inhibition.

3. The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model

Aron H Lichtman, William L Dewey, Laura E Wise, Hamid Akbarali, Travis W Grim, Jenny L Wilkerson, Matthew L Banks, Benjamin F Cravatt, Justin L Poklis, Micah J Niphakis, Rehab A Abdullah, Mohammed A Mustafa J Pharmacol Exp Ther . 2016 Apr;357(1):145-56. doi: 10.1124/jpet.115.229971.

Serious clinical liabilities associated with the prescription of opiates for pain control include constipation, respiratory depression, pruritus, tolerance, abuse, and addiction. A recognized strategy to circumvent these side effects is to combine opioids with other antinociceptive agents. The combination of opiates with the primary active constituent of cannabis (Δ(9)-tetrahydrocannabinol) produces enhanced antinociceptive actions, suggesting that cannabinoid receptor agonists can be opioid sparing. Here, we tested whether elevating the endogenous cannabinoid 2-arachidonoylglycerol through the inhibition of its primary hydrolytic enzyme monoacylglycerol lipase (MAGL), will produce opioid-sparing effects in the mouse chronic constriction injury (CCI) of the sciatic nerve model of neuropathic pain. The dose-response relationships of i.p. administration of morphine and the selective MAGL inhibitor 2,5-dioxopyrrolidin-1-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate (MJN110) were tested alone and in combination at equieffective doses for reversal of CCI-induced mechanical allodynia and thermal hyperalgesia. The respective ED50 doses (95% confidence interval) of morphine and MJN110 were 2.4 (1.9-3.0) mg/kg and 0.43 (0.23-0.79) mg/kg. Isobolographic analysis of these drugs in combination revealed synergistic antiallodynic effects. Acute antinociceptive effects of the combination of morphine and MJN110 required μ-opioid, CB1, and CB2 receptors. This combination did not reduce gastric motility or produce subjective cannabimimetic effects in the drug discrimination assay. Importantly, combinations of MJN110 and morphine given repeatedly (i.e., twice a day for 6 days) continued to produce antiallodynic effects with no evidence of tolerance. Taken together, these findings suggest that MAGL inhibition produces opiate-sparing events with diminished tolerance, constipation, and cannabimimetic side effects.

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