Radioprotective and antitumor activity evaluation of newly synthesized adamantyl tenocyclidines.

Several adamantyl derivatives of thienyl phencyclidine (tenocyclidine; TCP) were newly sythesized and characterized: adamantyl derivatives containing piperidine (TAPIP), pyrrolidine (TAPYR), and morpholine (TAMORPH) groups. Their biological activity was evaluated by in vitro testing of their effect on the proliferative and reproductive ability (cytotoxicity) of a human tumor cell strain and nonmalignant mouse fibroblasts in culture. We also tested them for their radioprotective effect after ionizing irradiation, and as anticancer agents on the same human tumor cell strain. Compared with TCP, adamantyl derivatives are less toxic and have outstanding radioprotective properties. These derivatives (especially TAMORPH) increase apoptotic death of human malignant cells. The radiation-modifying effect studied on C3Hf mice in vivo showed that the adamantyl derivatives of TCP have a more enhanced radioprotective effect and that they are less toxic than TCP itself. The present data are discussed and compared with those previously reported for structurally related phencyclidine derivatives.

Adamantyl tenocyclidines--adjuvant therapy in poisoning with organophosphorus compounds and carbamates.

The objective of this study was to evaluate the efficacy of thienyl phencyclidine (tenocyclidine, TCP) and its newly synthesized adamantyl derivatives containing piperidine (TAPIP), pyrolidine (TAPIR) and morpholine (TAMORF) groups, which were tested with or without standard therapy in mice poisoned with organophosphates (OPs) and carbamates. These compounds with potential activity at the N-methyl- D-aspartate and muscarinic receptors showed low acute toxicity, having LD50 values varying from 106.00 mg/kg (TCP) to >504.00 mg/kg body weight (TAMORF). TCP and its adamantyl derivatives were administered intraperitoneally (2.5 mg/kg body weight) together with atropine (10.0 mg/kg body weight) and with or without 1/4 LD50 of the oxime HI-6. Each compound administered with atropine had a therapeutic effect against poisoning with carbamates propoxur, aldicarb and Ro 02-0683 (protective ratio of tenocyclidines was from 3.99 LD50 of aldicarb to >16.00 LD50 for propoxur). However, the efficacy of those compounds in combination with atropine was lower against poisoning with the OP insecticide dichlorvos (DDVP) and chemical warfare agents soman and tabun. In soman-poisoned mice, the best therapeutic effects were obtained with the combination of HI-6 plus atropine and test compounds, with protective ratios being from 5.40 to 7.12 LD50 of soman. The results suggest that TCP and adamantyl tenocyclidines could be used in combination with atropine as antidotes in carbamate poisoning and as adjuvant therapy to HI-6 and atropine in soman poisoning.