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Biphalin

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Biphalin

Biphalin
Systematic (IUPAC) name
(2S,2’S)-N,N’-[(2R,8S,13S,19R)-8,13-Dibenzyl-3,6,9,12,15,18-hexaoxo-4,7,10,11,14,17-hexaazaicosane-2,19-diyl]bis[2-amino-3-(4-hydroxyphenyl)propanamide]
Clinical data
Legal status
?
Identifiers
CAS number
ATC code None
PubChem
ChemSpider
Chemical data
Formula C46H56N10O10 
Mol. mass 908.998 g/mol

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.[1] 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.[2] 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.[3] 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;[2] 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[2] and in general 4,4' positions are found to be important to design biphalin analogues with increased potency and modified μ/δ selectivity.[4][5] The hydrazide linker is not fundamental for activity or binding, and it can be conveniently substituted by different conformationally constrained cycloaliphatic diamine linkers.[6]

References

  1. ^ Flippen-Anderson, Judith (March 2002). "Crystal structure of biphalin sulfate: a multireceptor opioid peptide". The Journal of Peptide Research 59 (3): 123–33.  
  2. ^ a b c 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.  
  3. ^ Horan, Peter (June 1993). "Antinociceptive Profile of Biphalin, a Dimeric Enkephalin Analog". The Journal of Pharmacology and Experimental Therapeutics 265 (3): 1446–54.  
  4. ^ 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.  
  5. ^ 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.  
  6. ^ Mollica, Adriano (May 2005). "Synthesis and biological evaluation of new biphalin analogues with non-hydrazine linkers". Bioorganic & Medicinal Chemistry Letters 15 (10): 2471–5.  


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