title: Pharmacological in vitro evaluation of new substance P-cyclodextrin derivatives designed to drug targeting towards NK1-receptor bearing cells.
abstract: Some biological properties of new bifunctional conjugates designed for drug targeting were evaluated through in vitro experiments. Eight peptidylcyclodextrin compounds were used, which correspond to modified beta- or gamma-cyclodextrin (CD) grafted on neuropeptide substance P (SP) or a shorter derivative (SP(4-11)). Using anti-SP and anti-CD antibodies as molecular probes, we showed that the main structural features of the two moieties of these adducts were preserved. Binding experiments, using CHO cells expressing the human SP-specific NK1 receptor, demonstrated the functionality of all peptidylcyclodextrin derivatives, which exhibited IC50 values in a 10(-9)-10(-7) M range. All compounds were able to induce a pharmacological response, triggering phosphatidylinositol turnover with EC50 values in the same range as the natural ligand. Moreover, autoradiography analysis of rat spinal corn sections proved that [125I]SP binding was dose-dependently displaced by one selected compound (a gamma-CD-SP), showing a similar affinity of this adduct for the rat neurokinin 1 receptor. Our observations demonstrate that these peptidylcyclodextrins efficiently target NK1 receptor-expressing cells.
authors.affiliation: CEA, DRECAM/SCM, CEA-Saclay, Gif-sur Yvette, France.
authors.forename: C
authors.initials: C
authors.lastname: Péan
authors.forename: A
authors.initials: A
authors.lastname: Wijkhuisen
authors.forename: F
authors.initials: F
authors.lastname: Djedaïni-Pilard
authors.forename: J
authors.initials: J
authors.lastname: Fischer
authors.forename: S
authors.initials: S
authors.lastname: Doly
authors.forename: M
authors.initials: M
authors.lastname: Conrath
authors.forename: J Y
authors.initials: JY
authors.lastname: Couraud
authors.forename: J
authors.initials: J
authors.lastname: Grassi
authors.forename: B
authors.initials: B
authors.lastname: Perly
authors.forename: C
authors.initials: C
authors.lastname: Créminon
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D001345:Autoradiography; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003505:Cyclodextrins / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D016503:Drug Delivery Systems; D015195:Drug Design; D015394:Molecular Structure; D018040:Receptors, Neurokinin-1 / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis; D013373:Substance P / Q000031:analogs & derivatives* / Q000737:chemistry / Q000276:immunology; D047392:beta-Cyclodextrins; D047408:gamma-Cyclodextrins
chemical_list: D000906:Antibodies; D003505:Cyclodextrins; D018040:Receptors, Neurokinin-1; D011994:Recombinant Proteins; D047392:beta-Cyclodextrins; D047408:gamma-Cyclodextrins; D013373:Substance P; C031215:betadex; C023792:gamma-cyclodextrin