Abstract：

Of endogenous opioid peptides, enkephalins, dermorphins, endorphins and endomorphins, endomorphins exhibit high μ-opioid receptor affinity and extraordinarily high selectivity over δ- and κ-receptors, indicating the important roles of μ-opioid receptor-ligand system. Those opioid peptides are potential candidates of analgesics for clinical and therapeutic use for the amelioration of pain associated with postsurgery procedure, cancer or birth. However, the oral availability of　bioactive peptides requires means not only to overcome physiological and metabolic barriers but also to be able to transit the physical barriers such as the epithelial membrane of the gastrointestinal tract and blood-brain barrier (BBB). While several amino acids were found to replace Tyr in opioid [1], 2’,6’-dimethyl-L-tyrosine (Dmt) dramatically enhanced receptor affinity and functional bioactivity. [Dmt¹]endomorphin-2 exhibited high μ- and δ-opioid receptor affinity (Kiμ = 0.15 and Kiδ = 28.2 nM) with corresponding agonisms (IC₅₀: 0.07 and 1.87 nM, respectively). Interestingly, although [N-Allyl-Dmt¹]endomorphin-2 bound with μ-opioid receptor (Kiμ = 0.45 nM), it showed μ- antagonist with pA₂ value of 8.59. With aims to increase bioavailability of opioids and opioidmimetics, dimerization of appropriate pharmacophore, such as Dmt, Dmt-Tic linked with diaminoalkane [2] and 3,6-bis[aminoalkyl]-pyrazinone derivative (Fig. 1) [3] was performed.          

The latter opioidmimetics containing Dmt as a pharmacophore exhibited potent antinociceptive activity after intracerebroventricular (i.c.v.), subcutaneous (s.c.) and oral (p.o.) administration in mice, indicating that they can pass through epithelial membrane of gastrointestinal tract and cross blood-brain barrier. Both type μ-agonists containing diaminoalkane and 3,6-bis[amino- alkyl]pyrazinone were transformed to potent μ-antagonist by allylation. Above potent  μ-antagonists are potential candidates for the drugs of drug addiction and alcohol dependency..

Fig. 1. Structure of Dmt dimmers linked with pyrazinone ring.

[1]  Li, T., Fujita, Y., Tsuda, Y., Mitazaki, A., Ambo, A., Sasaki, Y., Jinsmaa, Y., Bryanat, S.D., Lazarus, L.H., Okada, Y. J. Med. Chem. 2005, 48, 586--592.

[2]　Okada, Y., Tsuda, Y., Fujita, Y., Yokoi, T., Sasaki, Y., Ambo, A., Konishi, R., Nagata, M., Salvadori, S., Yunden, J., Bryant, S. D., Lazarus, L. H. J. Med. Chem. 2003, 46, 3201-3209.

[3]  Jinsmaa, Y., Miyazaki, A., Fujita, Y., Fujisawa, Y., Shiotani, K., Li, T., Tsuda, Y., Yokoi, T., Ambo, A., Sasaki, Y., Bryant, S. D., Lazarus, L. H. and Okada, Y. J. Med. Chem. 47, 2599-2610 (2004)