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Naloxone benzoylhydrazone (NalBzoH) has proved a valuable tool in the investigation of opioid receptor subtypes. In the present study, we have examined a series of derivatives of NalBzoH in which substitutions have been made on the benzoyl ring. Overall, we see dramatic effects on the binding affinities of derivatives against the various opioid receptor subtypes. Although the range of affinities against the mu receptors is quite modest, ranges of the others vary almost 30-fold for kappa 3, 50-fold for kappa 1 and 100-fold for delta and kappa 2 binding. Few substituted derivatives display greater affinity than NalBzoH for any of the receptors, except for delta sites where several derivatives have affinities almost tenfold greater than NalBzoH. Along with the wide variations in affinity, the compounds also appear to exhibited widely divergent activities in traditional bioassays.

A series of DNA-intercalating 9-anilinoacridines, namely 9-phenoxyacridines, 9-(phenylthio)acridines, and 9-(3',5'-disubstituted anilino)acridines, were synthesized as potential antitumor agents with inhibitory effects on DNA topoisomerase II. Unlike amsacrine (m-AMSA), these agents were designed to avoid the oxidative metabolic pathway. These acridine derivatives were, therefore, expected to have long half-life in plasma. Both 9-phenoxyacridines and 9-(phenylthio)acridines were found to have moderate cytotoxicity against mouse leukemia L1210 and human leukemic HL-60 cell growth in culture. Among 9-(3',5'-disubstituted anilino)acridines, 3-(9-acridinylamino)-5-(hydroxymethyl)aniline (AHMA) was found to be a potent topoisomerase II inhibitor and exhibited significant antitumor efficacy both in vitro and in vivo. Chemotherapy of solid-tumor-bearing mice with 10, 10, and 5 mg/kg (QD x 4, ip) AHMA, VP-16, and m-AMSA, respectively, resulted in more tumor volume reduction by AHMA than by VP-16 or m-AMSA for E0771 mammary adenocarcinoma and B-16 melanoma. For Lewis lung carcinoma, AHMA was as potent as VP-16 but more active than m-AMSA. Structure-activity relationships of AHMA derivatives are discussed.

Opiate receptor expression in phylogenetically different species has played an important role in the study of opioid receptor pharmacology. Total opioid binding measured with the nonselective ligand 3H-diprenorphine reveals a Bmax of 21.7 +/- 1.37 fmol/mg tissue wet wt and a KD of 0.17 +/- 0.03 nM in Bufo marinus (giant toad), as well as a Bmax of 18.17 + 0.41 fmol/mg tissue wet wt and a KD of 0.47 +/- 0.18 nM in Carassius auratus (goldfish). Despite the similar levels of 3H-diprenorphine binding, the composition of binding subtypes in the two species differs. Approximately 30% of total binding corresponds to mu receptors in both species, whereas neither kappa 1 nor delta binding can be detected. However, the remaining 70% of binding differs between the toad and goldfish. In the toad, the non-mu binding corresponds to kappa 2 sites, whereas in the goldfish, the non-mu binding corresponds to kappa 3 sites. The sites can be distinguished biochemically, as well as pharmacologically. After affinity labeling the sites with 3H-NalBzoH, the retention times on an ion-exchange column differ for the peaks of kappa binding in the two species. Although Bufo marinus (giant toad) and Carassius auratus (goldfish) brains express kappa and mu opioid binding, the kappa subtypes in these two species differ.

In connection with the increased incidence of cataract in middle-aged patients investigations were carried out in order to clear up one of the possible causes of this condition. The detection of a substantial decrease of galactose-1-phosphate uridyl transferase activity in patients with presenile cataract evidences the disturbance of galactose metabolism these patients and allows to accept this genetic defect as the causes of opacification of the lens. Attention was called to the eventual importance of these investigations because of the adoption of a diet without galactose in person threatened+ by cataract could prevent or check this disease.