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Synthesis, Biological Activity and Molecular Modeling Studies of 1,2,3,4-tetrahydroisoquinoline Derivatives as Conformationally Constrained Analogues of KN62, a Potent Antagonist of the P2X7-receptor Containing a Tyrosine Moiety

Synthesis, Biological Activity and Molecular Modeling Studies of 1,2,3,4-tetrahydroisoquinoline Derivatives as Conformationally Constrained Analogues of KN62, a Potent Antagonist of the P2X7-receptor Containing a Tyrosine Moiety

Pier Giovanni Baraldi, Rimma Makaeva, Maria Giovanna Pavani, Maria del Carmen Nuñez, Giampiero Spalluto, Stefano Moro, Simonetta Falzoni, Francesco Di Virgilio, Romeo Romagnoli

Arzneimittelforschung. 2002;52(4):273-85.

PMID: 12040970

Abstract:

A new series of ring constrained analogues of the P2X7 receptor antagonist KN62 (1-[N,O-bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4- phenylpiperazine, CAS 127191-97-3) containing the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid core with S configuration in position 3 was synthesised and their antagonist activities were tested on human macrophage cells. While KN62 is a potent antagonist of the P2X7 receptor, these novel compounds are weak antagonists of the purinergic P2X7 receptor and only one compound (5) showed appreciable activity as P2X7 antagonist, which was 30 times weaker than that reported for KN62. Along with compound 5, the derivatives 11 and 25 were the most active inhibitors in this synthesised series. A molecular modeling study confirmed that an extended rather than folded conformation seems to be crucial for the antagonistic activity at the P2X7 receptor.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP127191973-B	KN-62 - CAS 127191-97-3		127191-97-3	Price

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