Bridged Piperidine Analogues of a High Affinity Naphthalene-Based P2Y₁₄R Antagonist.

ABSTRACT: High affinity phenyl-piperidine P2Y₁₄R antagonist 1 (PPTN) was modified with piperidine bridging moieties to probe receptor affinity and hydrophobicity. Various 2-azanorbornane, nortropane, isonortropane, isoquinuclidine, and ring-opened cyclopentylamino derivatives preserved human P2Y₁₄R affinity (fluorescence binding assay), and their pharmacophoric overlay was compared. Enantiomeric 2-azabicyclo[2.2.1]hept-5-en-3-one precursors assured stereochemically unambiguous, diverse products. Pure (S,S,S) 2-azanorbornane enantiomer 15 (MRS4738) displayed higher affinity than 1 (3-fold higher affinity than enantiomer 16) and in vivo antihyperallodynic and antiasthmatic activity. Its double prodrug 143 (MRS4815) dramatica

SUBMITTER: Wen Z 

PROVIDER: S-EPMC8881401 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature