title: Structural and biological exploration of phe(3)-phe(4)-modified endomorphin-2 peptidomimetics.
abstract: This study reports on our ongoing investigation on hybrid EM-2 analogues, in which the great potential of β-amino acids was exploited to generate multiple conformational modifications at the key positions 3 and 4 of the parent peptide. The effect on the opioid binding affinity was evaluated, by means of ligand stimulated binding assays, which indicated a high nanomolar affinity toward the μ-receptor, with appreciable μ/δ selectivity, for some of the new compounds. The three-dimensional properties of the high affinity μ opioid receptor (MOR) ligands were investigated by proton nuclear magnetic resonance, molecular dynamics, and docking studies. In solution, the structures showed extended conformations, which are in agreement with the commonly accepted pharmacophore model for EM-2. From docking studies on an active form of the MOR model, different ligand-receptor interactions have been identified, thus confirming the ability of active compounds to assume a biologically active conformation.
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano , via C. Golgi, 19, 20133 Milano, Italy.
authors.forename: Giordano
authors.initials: G
authors.lastname: Lesma
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Ferrara , via Fossato di Mortara 17-19, 44100 Ferrara, Italy.
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano , via C. Golgi, 19, 20133 Milano, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Airaghi
authors.affiliation: Department of Pharmacology, Creighton University School of Medicine , Omaha, Nebraska 68102, United States.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Murray
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano , via C. Golgi, 19, 20133 Milano, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Recca
authors.affiliation: Dipartimento di Chimica, Materiali ed Ingegneria Chimica 'Giulio Natta' , Politecnico di Milano, p.zza Leonardo da Vinci 32, 20133 Milano, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sacchetti
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Università degli Studi di Cagliari , Via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Balboni
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano , via C. Golgi, 19, 20133 Milano, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Silvani
keywords: Peptidomimetics; conformational analysis; docking studies; opioid receptors; β-amino acids