title: Novel cyclic biphalin analogue with improved antinociceptive properties.
abstract: Two novel opioid analogues have been designed by substituting the native d-Ala residues in position 2,2' of biphalin with two residues of d-penicillamine or l-penicillamine and by forming a disulfide bond between the thiol groups. The so-obtained compound 9 containing d-penicillamines showed excellent μ/δ mixed receptor affinities (K i (δ) = 5.2 nM; K i (μ) = 1.9 nM), together with an efficacious capacity to trigger the second messenger and a very good in vivo antinociceptive activity, whereas product 10 was scarcely active. An explanation of the two different pharmacological behaviors of products 9 and 10 was found by studying their conformational properties.
authors.affiliation: Dipartimento di Farmacia, Università di Chieti-Pescara "G. d'Annunzio" , Via dei Vestini, 31, 66100 Chieti, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Mollica
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II" , Via D. Montesano, 49, 80131 Naples, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Carotenuto
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II" , Via D. Montesano, 49, 80131 Naples, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II" , Via D. Montesano, 49, 80131 Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Limatola
authors.affiliation: Dipartimento di Farmacia, Università di Chieti-Pescara "G. d'Annunzio" , Via dei Vestini, 31, 66100 Chieti, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Costante
authors.affiliation: Dipartimento di Farmacia, Università di Chieti-Pescara "G. d'Annunzio" , Via dei Vestini, 31, 66100 Chieti, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pinnen
authors.affiliation: Dipartimento di Chimica, Sapienza, Università di Roma , P.le A. Moro, 5, 00187 Rome, Italy.
authors.forename: Azzurra
authors.initials: A
authors.lastname: Stefanucci
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità , V.le Regina Elena 299, 00161 Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Pieretti
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences , 6726 Szeged, Hungary.
authors.forename: Anna
authors.initials: A
authors.lastname: Borsodi
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences , 6726 Szeged, Hungary.
authors.forename: Reza
authors.initials: R
authors.lastname: Samavati
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences , 6726 Szeged, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Zador
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences , 6726 Szeged, Hungary.
authors.forename: Sándor
authors.initials: S
authors.lastname: Benyhe
authors.affiliation: Department of Pharmacology and Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Peg
authors.initials: P
authors.lastname: Davis
authors.affiliation: Department of Pharmacology and Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.affiliation: Department of Pharmacology and Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
keywords: Analgesics; biphalin; cyclic analogues; dimeric opioid peptides