Structure−Activity Relationships of Lysophosphatidic Acid:  Conformationally Restricted Backbone Mimetics

• Published in: Journal of medicinal chemistry Vol. 42; no. 6; pp. 963 - 970
• Main Authors: Hopper, Darrin W, Ragan, Seamus P, Hooks, Shelley B, Lynch, Kevin R, Macdonald, Timothy L
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.03.1999; Amer Chemical Soc
• Subjects: Biological and medical sciences; Calcium - metabolism; Chemistry, Medicinal; Humans; Life Sciences & Biomedicine; Lysophospholipids - chemical synthesis; Lysophospholipids - chemistry; Lysophospholipids - pharmacology; Medical sciences; Miscellaneous; Molecular Conformation; Molecular Mimicry; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Receptors, Cell Surface - drug effects; Receptors, G-Protein-Coupled; Receptors, Lysophosphatidic Acid; Science & Technology; Structure-Activity Relationship; Tumor Cells, Cultured; RECEPTOR; Human; Molecular rigidity; Benzophenone derivatives; Fatty ester; Phospholipid; Steric hindrance; Epithelium; Complex lipid; Fatty acids; In vitro; Phosphorus Organic compounds; Biological fixation; Cell line; Lysophosphatidic acid; Structure activity relation; Organic phosphate; Chemical synthesis; Biological receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970809v

Lysophosphatidic acid (LPA) has associated with it an intriguing cell biology that is thought to be mediated through its interaction with G-protein coupled receptor(s). In an effort to extend the structure−activity relationships of LPA, we have produced a series of LPA analogues in which the glycerol core in LPA was replaced with conformationally restricted aryl substructures. The aryl substructures encompassed aminophenol, resorcinol, dihydroxy benzophenone, and tocopherol systems. The benzophenone moiety was investigated both as a conformationally restricting substructure for LPA and as a possible photoreactive alkylating agent for the LPA receptor(s). All LPA analogues were evaluated for their potency and efficacy in mobilizing calcium ions from internal stores in MDA MB-231 cells. Ten of the 14 analogues exhibited activity in this assay at doses up to 5 μM; none of the compounds exhibited nonreceptor-mediated lytic activity at this maximal concentration. The receptor response showed surprising tolerance for manipulation in the backbone region of LPA, although none of the compounds were equipotent to LPA. This tolerance for a variety of structures has given us new leads into the realization of novel agonists and antagonists of the LPA receptor(s).