Biphalin

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 pharmacophores confers on biphalin a high affinity for both μ and δ opioid receptors (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; biphalin and morphine were found to be equipotent after intraperitoneal administration. The extraordinary in vivo potency shown 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 information about structure-activity relationship (SAR). Results clearly indicate that, at least for μ receptor binding, the presence of two pharmacophores is not necessary;[2] Tyr1 is indispensable for analgesic activity, while replacing Phe at the position 4 and 4' with non-aromatic, but lipophilic amino acids does not greatly change the binding properties[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]

Biphalin
Clinical data
ATC code
  • None
Identifiers
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]
CAS Number
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC46H56N10O10
Molar mass909.014 g·mol−1
3D model (JSmol)
SMILES
  • O=C(N[C@@H](C(=O)NCC(=O)N[C@H](C(=O)NNC(=O)[C@@H](NC(=O)CNC(=O)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C)Cc2ccccc2)Cc3ccccc3)C)[C@@H](N)Cc4ccc(O)cc4
InChI
  • InChI=1S/C46H56N10O10/c1-27(51-43(63)35(47)21-31-13-17-33(57)18-14-31)41(61)49-25-39(59)53-37(23-29-9-5-3-6-10-29)45(65)55-56-46(66)38(24-30-11-7-4-8-12-30)54-40(60)26-50-42(62)28(2)52-44(64)36(48)22-32-15-19-34(58)20-16-32/h3-20,27-28,35-38,57-58H,21-26,47-48H2,1-2H3,(H,49,61)(H,50,62)(H,51,63)(H,52,64)(H,53,59)(H,54,60)(H,55,65)(H,56,66)/t27-,28-,35+,36+,37+,38+/m1/s1
  • Key:DESSEGDLRYOPTJ-VRANXALZSA-N

References
  1. Flippen-Anderson JL, Deschamps JR, George C, Hruby VJ, Misicka A, Lipkowski AW (March 2002). "Crystal structure of biphalin sulfate: a multireceptor opioid peptide". The Journal of Peptide Research. 59 (3): 123–33. doi:10.1034/j.1399-3011.2002.01967.x. PMID 11985706.
  2. Lipkowski AW, Misicka A, Davis P, Stropova D, Janders J, Lachwa M, et al. (September 1999). "Biological activity of fragments and analogues of the potent dimeric opioid peptide, biphalin". Bioorganic & Medicinal Chemistry Letters. 9 (18): 2763–6. doi:10.1016/S0960-894X(99)00464-3. PMID 10509931.
  3. Horan PJ, Mattia A, Bilsky EJ, Weber S, Davis TP, Yamamura HI, et al. (June 1993). "Antinociceptive profile of biphalin, a dimeric enkephalin analog". The Journal of Pharmacology and Experimental Therapeutics. 265 (3): 1446–54. PMID 8389867.
  4. Li G, Haq W, Xiang L, Lou BS, Hughes R, De Leon IA, et al. (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.
  5. Mollica A, Pinnen F, Feliciani F, Stefanucci A, Lucente G, Davis P, et al. (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. PMC 5689474. PMID 20924622.
  6. Mollica A, Davis P, Ma SW, Lai J, Porreca F, Hruby VJ (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.
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