PMID- 12191582
OWN - NLM
STAT- MEDLINE
DCOM- 20030121
LR  - 20190624
IS  - 0014-2999 (Print)
IS  - 0014-2999 (Linking)
VI  - 444
IP  - 1-2
DP  - 2002 May 24
TI  - Role of spin trapping and P2Y receptor antagonism in the neuroprotective effects 
      of 2,2'-pyridylisatogen tosylate and related compounds.
PG  - 53-60
AB  - 2,2'-Pyridylisatogen tosylate (PIT) is both an allosteric modulator of P2Y 
      receptors, and an immine oxide, acting as a spin trap for free radicals. PIT (10 
      mg kg(-1), i.p.) was found to be a powerful neuroprotective agent in protecting 
      against the lesions induced by 15 micro g S-bromo-willardiine injected into the 
      cortex or white matter of 5-day-old mice pups. As the multiple effects of PIT may 
      induce both beneficial and deleterious effects, a reanalysis of the 
      structure-activity relationship was undertaken. PIT (50 micro M) and 
      2,3'-pyridylisatogen were potent antagonists of responses to ATP in the taenia 
      preparation of the guinea-pig caecum, but 2,3'-nitrophenylisatogen was not. The 
      reactive immine oxide group could be substituted by a keto moiety 
      (N-(2'-pyridyl)phthalide) while maintaining antagonism of responses to ATP, 
      equivalent to PIT. Thus, antagonism of P2Y receptors was not restricted to the 
      isatogen nucleus. Other spin traps did not antagonise P2Y receptors, although 
      dimethyl-pyrroline-N-oxide (DMPO) increased the sensitivity of responses to ATP. 
      Both N-(2'-pyridyl)phthalide and 2,3'-nitrophenylisatogen was less 
      neuroprotective than PIT (10 mg kg(-1), i.p.) in protecting against the 
      S-bromo-willardiine-induced lesions in mice, implying that both antagonism of P2Y 
      receptors and the immine oxide moiety may be important for the neuroprotective 
      effects of PIT. However, the usefulness of the neuroprotection was limited 
      because, in motoneurones obtained from rat embryos, PIT (10-100 micro M) 
      exacerbated cell death.
FAU - Menton, Kevin
AU  - Menton K
AD  - Institute of Pharmacy, Chemistry and Biomedical Sciences, School of Sciences, 
      University of Sunderland, Sunderland, SR1 3SD, UK.
FAU - Spedding, Michael
AU  - Spedding M
FAU - Gressens, Pierre
AU  - Gressens P
FAU - Villa, Pascal
AU  - Villa P
FAU - Williamson, Toni
AU  - Williamson T
FAU - Markham, Anthony
AU  - Markham A
LA  - eng
PT  - Journal Article
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Purinergic P2 Receptor Antagonists)
RN  - 56583-49-4 (2,2'-pyridylisatogen tosylate)
RN  - 82X95S7M06 (Isatin)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Guinea Pigs
MH  - Isatin/*analogs & derivatives/*pharmacology
MH  - Mice
MH  - Motor Neurons/*drug effects
MH  - Muscle Contraction/*drug effects
MH  - Muscle, Smooth/*drug effects
MH  - Neuroprotective Agents/*pharmacology
MH  - *Purinergic P2 Receptor Antagonists
MH  - Spin Trapping
MH  - Structure-Activity Relationship
EDAT- 2002/08/23 10:00
MHDA- 2003/01/22 04:00
CRDT- 2002/08/23 10:00
PHST- 2002/08/23 10:00 [pubmed]
PHST- 2003/01/22 04:00 [medline]
PHST- 2002/08/23 10:00 [entrez]
AID - S0014299902015832 [pii]
AID - 10.1016/s0014-2999(02)01583-2 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2002 May 24;444(1-2):53-60. doi: 10.1016/s0014-2999(02)01583-2.