Compound: Biphalin
SMILES: O=C(NNC(=O)[C@@H](NC(=O)CNC(=O)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C)Cc2ccccc2)[C@@H](NC(=O)CNC(=O)[C@H](NC(=O)[C@@H](N)Cc3ccc(O)cc3)C)Cc4ccccc4
InChIKey: DESSEGDLRYOPTJ-VRANXALZSA-N
Synonyms: Biphalin, 83916-01-2, (Tyr-ala-gly-phe-NH2)2, D-Enk-O, Dala(2), D-ENK, Bis(tyr-ala-gly-phenh2)hydrazide, (Tyrosyl-alanyl-glycyl-phenylalaninamide)dimer, Bis(tyrosyl-alanyl-glycyl-phenylalaninamide)hydrazide, DTXSID80232802, RefChem:119905, DTXCID70155293, CHEMBL200199, (2S)-2-amino-N-[(2R)-1-[[2-[[(2S)-1-[2-[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]propanoyl]amino]acetyl]amino]-3-phenylpropanoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]amino]-1-oxopropan-2-yl]-3-(4-hydroxyphenyl)propanamide, L-Phenylalanine, N-(N-(N-L-tyrosyl-D-alanyl)glycyl)-, 2-(N-(N-(N-L-tyrosyl-D-alanyl)glycyl)-L-phenylalanyl)hydrazide, enkephalin dimer, L-Phenylalanine, N-[N-(N-L-tyrosyl-D-alanyl)glycyl]-, 2-[N-[N-(N-L-tyrosyl-D-alanyl)glycyl]-L-phenylalanyl]hydrazide, 4QHN3LYD63, orb1987107, Biphalin trifluoroacetate salt (, SCHEMBL29582936, BDBM21014, AKOS040746625, (2S)-2-AMINO-N-[(1R)-1-[({[(1S)-1-{N'-[(2S)-2-{2-[(2R)-2-[(2S)-2-AMINO-3-(4-HYDROXYPHENYL)PROPANAMIDO]PROPANAMIDO]ACETAMIDO}-3-PHENYLPROPANOYL]HYDRAZINECARBONYL}-2-PHENYLETHYL]CARBAMOYL}METHYL)CARBAMOYL]ETHYL]-3-(4-HYDROXYPHENYL)PROPANAMIDE, (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), FB110181, H-Tyr-D-Ala-Gly-Phe-NH)2 trifluoroacetate salt, Q3639770, (2R,2'R)-N,N'-(Hydrazine-1,2-diylbis{[(2S)-1-oxo-3-phenylpropane-1,2-diyl]azanediyl(2-oxoethane-2,1-diyl)})bis{2-[(2S)-2-amino-3-(4-hydroxyphenyl)propanamido]propanamide}, (2S)-2-amino-N-[(1R)-1-[({[(1S)-1-{N''-[(2S)-2-{2-[(2R)-2-[(2S)-2-amino-3-(4-hydroxyphenyl)propanamido]propanamido]acetamido}-3-phenylpropanoyl]hydrazinecarbonyl}-2-phenylethyl]carbamoyl}methyl)carbamoyl]ethyl]-3-(4-hydroxyphenyl)propanamide, L-Phenylalanine, L-tyrosyl-D-alanylglycyl-, 2-(L-tyrosyl-D-alanylglycyl-L-phenylalanyl)hydrazide
Theoretical properties:
molecular_formula: C46H56N10O10
molecular_weight: 909.0 g/mol
exact_mass: 908.41808802 g/mol
formal_charge: 0
hydrogen_bond_donor_count: 12
hydrogen_bond_acceptor_count: 12
rotatable_bond_count: 22
heavy_atom_count: 66
topological_polar_surface_area: 325 Å²
isotope_atom_count: 0
covalently_bonded_unit_count: 1
Physical properties:
Descriptions:
chembl: BIPHALIN is a small molecule listed in the ChEMBL database but has not progressed to an approved clinical phase.
wikipedia: 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 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.
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. 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; 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 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.