title: Structure-activity relationships of biphalin analogs and their biological evaluation on opioid receptors.
abstract: Biphalin (Tyr-D-Ala-Gly-Phe-NH-NH < -Phe < -Gly < -D-Ala < -Tyr) is an opioid octapeptide with a dimeric structure based on two identical pharmacophore portions, derived from enkephalins, joined "tail to tail" by a hydrazide bridge. This particular structure enhances the antinociceptive activity of the native enkephalins with an unknown mechanism, probably based on a cooperative binding and improved enzymatic stability. Biphalin has excellent binding affinity for μ and δ receptors and it is a highly potent analgesic, as potent as or more than ethorphine. A definitive explanation of the extraordinary in vivo potency shown by this compound, which has pronounced efficacy in pain modulation, is still not available; it has been suggested, however, that the high agonist activity may be related to its binding mode at both μ and δ opioid receptors. Biphalin has significantly higher potency than other analgesics with novel biological profiles; in particular, most recent data show that biphalin is unlikely to produce dependency in chronic use. In the past 20 years, there have been many attempts to modify its structure to obtain products unaffected by the action of enkephalinases, to enhance its antinociceptive activity and to modify the BBB penetration. In addition, structure-activity relationship studies (SAR) were performed in order to understand the elements responsible for biphalin's high activity. The aim of the studies reported in this review was to clarify: i) the role of the hydrazide bridge, ii) the role of residues in position 4, 4' and 3, 3', iii) the consequences of molecular simplifications (truncation, delection), iv) the consequences of cyclization through a disulfide bridge, v) conjugation with PEG and fluorescet residues, and vi) radiolabeling on Tyr.
authors.affiliation: Dipartimento di Farmacia, Università di Chieti-Pescara G. d'Annunzio, Chieti, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Feliciani
authors.forename: Francesco
authors.initials: F
authors.lastname: Pinnen
authors.forename: Azzurra
authors.initials: A
authors.lastname: Stefanucci
authors.forename: Roberto
authors.initials: R
authors.lastname: Costante
authors.forename: Ivana
authors.initials: I
authors.lastname: Cacciatore
authors.forename: Gino
authors.initials: G
authors.lastname: Lucente
authors.forename: Adriano
authors.initials: A
authors.lastname: Mollica
mesh_terms: D000818:Animals; D004745:Enkephalins / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008968:Molecular Conformation; D011957:Receptors, Opioid / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D004745:Enkephalins; D011957:Receptors, Opioid; C053673:biphalin