Biphalin
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| Systematic (IUPAC) name | |
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(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]
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| Identifiers | |
| CAS Number | 83916-01-2 |
| ATC code | None |
| PubChem | CID 5487663 |
| ChemSpider | 4589475 |
| Chemical data | |
| Formula | C46H56N10O10 |
| Molar mass | 908.998 g/mol |
| 3D model (Jmol) | Interactive image |
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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 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; 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 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 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]
References[edit]
- ^ Flippen-Anderson, Judith (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.
- ^ 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. 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.
