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We re-examined the accessory site of the 4,5-epoxymorphinan skeleton by camdas conformational analysis in an effort to deign novel delta opioid receptor antagonists. We synthesized three novel compounds (SN-11, 23 and 28) with a 10-methylene bridge and without a 4,5-epoxy ring. Among them, compounds SN-23 (17-isobutyl derivative) and SN-28 (17-methyl derivative) showed very strong agonist activity (over 10 times more than TAN-67). SN-28 also showed high delta selectivity. The delta agonist activity of SN-23 was weaker than that of SN-28, but in terms of the delta selectivity, SN-23 was higher than that of SN-28. These unexpected results indicated that the 4,5-epoxy ring, but not the 10-methylene bridge, was an accessory site in delta opioid receptor agonists.

Selective ring opening reaction of the N-cyclopropylmethyl group in naltrexone (1d) was effected in the presence of platinum (IV) oxide and hydrobromic acid under a hydrogen atmosphere at rt to selectively afford N-isobutyl derivative 10. The binding affinity of N-i-Bu derivative 10 for opioid receptors was 11–17 times less than that of the corresponding N-CPM compound, naltrexone (1d). However, compound 10 showed dose-dependent analgesic effects. Contrary to expectations based on previous structure–activity relationship studies for a series of N-substituted naltrexone derivatives that compound 10 would be an opioid antagonist, 10 showed dose-dependent analgesia in the mouse acetic acid writhing test (ED50: 5.05 mg/kg, sc), indicating it was an opioid agonist. This finding may have a great influence on the drug design of opioid agonists.

The treatment of morphinan 1 with NaH and MsCl provided very stable iminium salt 7 possessing propellane skeleton. One of the synthesized iminium salts 7, isobutyl derivative 7b, was crystallized and its structure was determined by X-ray crystallography. The natural bond orbital analysis suggested that the stability of the iminium should result from the stereoelectronic effect (hyperconjugation) attributed to their own structures.

A novel 6,14-epoxymorphinan benzamide derivative (NS22) was synthesized, which showed opioid kappa receptor agonistic activity in the [(35)S]GTPgammaS binding assay. The antinociceptive effect of NS22 was evaluated in the tail-flick and the hot-plate test. This compound showed a potent antinociceptive activity in mice by s.c. administration, which was attenuated with nor-BNI (selective opioid kappa receptor antagonist).

Development of a sand spit can frequently be observed at river mouths where sediment transport by wave action is more predominant as compared with flushing ability by tidal and river discharge. Progress of river mouth closure may cause reduction in flow through a river opening, resulting in increase in infiltration flow through a sand spit at a river entrance due to distinct water level difference between inside and outside of a river mouth. However, there have been quite few investigation on this type of flow, although there have been many on coastal aquifer in connection with salinity intrusion and beach stabilization by dewatering of coastal aquifer. In the present study, results of field observation of infiltration flow in a sand spit at the mouth of Nanakita River are described. Comprehensive numerical simulation is also performed to investigate the effect of water level variation in the mouth on the strength of infiltration flow.