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| Formula | C46H56N10O10 |
| Molar mass | 909.014 g·mol−1 |
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Biphalin is adimericenkephalin endogenous peptide (Tyr-D-Ala-Gly-Phe-NH)2 composed of two tetrapeptides derived fromenkephalins, connected 'tail-to-tail' by ahydrazide bridge.[1] The presence of two distinct pharmacophores confers on biphalin a high affinity for bothμ andδ opioid receptors (with an EC50 of about 1–5 nM for both μ and δ receptors), therefore it hasanalgesic activity.[2]Biphalin presents a considerableantinociceptive profile. In fact, when administeredintracerebroventricularly in mice, biphalin displays a potency almost 7-fold greater than that of the ultra-potentalkaloid agonist,etorphine and 7000-fold greater thanmorphine; biphalin and morphine were found to be equipotent afterintraperitoneal administration. The extraordinary in vivo potency shown by this compound is coupled with low side-effects, in particular, to produce nodependency 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 receptorbinding, the presence of two pharmacophores is not necessary;[2]Tyr1 is indispensable for analgesic activity, while replacingPhe at the position 4 and 4' with non-aromatic, butlipophilic 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]
