|Systematic (IUPAC) name|
Biphalin is a dimeric enkephalin endogenous peptide (Tyr-D-Ala-Gly-Phe-NH)2 composed of two tetrapeptides derived from enkephalins, connected 'tail-to-tail' by a hydrazide bridge. The presence of two distinct pharmacophore confers of Biphalin highly affinity for both μ and δ opioid receptors (with a with an EC50 of about 1-5 nM for both μ and δ receptors), therefore it has analgesic activity. Biphalin presents a considerable antinociceptive profile. In fact, when administered intracerebroventricularly in mice, biphalin displays a potency almost 7-fold greater than that of the ultra-potent alkaloid agonist, etorphine and 7000-fold greater than morphine, and biphalin and morphine were found to be equipotent after intraperitoneal administration. The extraordinary in vivo potency showed by this compound is coupled with low side-effects, in particular to produce no dependency in chronic use. For these reasons, several efforts have been carried out in order to obtain more informations about structure-activity relationship (SAR). Results clarely indicates that at least for μ receptor binding the presence of two pharmacophores is not necessary; Tyr1 is indipensable for analgesic activity, while replacing Phe at the position 4 and 4' with non-aromatic, but lipophylic amino acids does not greatly change the binding proprieties and in general 4,4' positions are found to be important to design biphalin analogues with increased potency and modified μ/δ selectivity. The hydrazide linker is not fundamental for activity or binding, and it can be conveniently substituted by different conformationally constrained cycloaliphatic diamine linkers.
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- Lipkowski, Andrzej (September 1999). "Biological activity of fragments and analogues of the potent dimeric opioid peptide, biphalin". Bioorganic & Medicinal Chemistry Letters 9 (18): 2763–66. doi:10.1016/S0960-894X(99)00464-3. PMID 10509931.
- Horan, Peter (June 1993). "Antinociceptive Profile of Biphalin, a Dimeric Enkephalin Analog". The Journal of Pharmacology and Experimental Therapeutics 265 (3): 1446–54. PMID 8389867.
- Li, Guigen (March 1998). "Modifications of the 4,4'-residues and SAR studies of Biphalin, a highly potent opioid receptor active peptide". Bioorganic & Medicinal Chemistry Letters 8 (5): 555–60. doi:10.1016/S0960-894X(98)00065-1. PMID 9871617.
- Mollica, Adriano (May 2011). "New potent biphalin analogues containing p-fluoro-L-phenylalanine at the 4,4' positions and non-hydrazine linkers". Amino Acids 40 (5): 1503–11. doi:10.1007/s00726-010-0760-7. PMID 20924622.
- Mollica, Adriano (May 2005). "Synthesis and biological evaluation of new biphalin analogues with non-hydrazine linkers". Bioorganic & Medicinal Chemistry Letters 15 (10): 2471–5. doi:10.1016/j.bmcl.2005.03.067. PMID 15863299.