In vitro biological efficiency of tenocyclidine – TCP and its adamantane derivative TAMORF

• Published in: Toxicology in vitro 2006-12, Vol.20 (8), p.1455-1464
• Main Authors: Radić, Božica, Vrdoljak, Ana Lucić, Petek, Maja Jelena, Kopjar, Nevenka, Želježić, Davor
• Format: Article
• Language: English
• Subjects: Acetyl cholinesterase; Adamantane; Adamantane - analogs & derivatives; Adamantane - pharmacology; Cell Survival - drug effects; Cholinesterase Inhibitors - toxicity; Cholinesterase Reactivators - pharmacology; Chromosome Aberrations - drug effects; Comet Assay; Cytotoxicity; Erythrocytes - drug effects; Erythrocytes - enzymology; Gamma Rays; Humans; In Vitro Techniques; Lethal Dose 50; Leukocytes - drug effects; Leukocytes - radiation effects; Lymphocytes - drug effects; Morpholines - pharmacology; Mutagens - toxicity; Phencyclidine - analogs & derivatives; Piperidines - pharmacology; Radiation-Protective Agents - pharmacology; Radioprotector; Soman - antagonists & inhibitors; Soman - toxicity; Structure-Activity Relationship; Tenocyclidine; Thiophenes - pharmacology; Trypan Blue
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2006.07.002

Tenocyclidine – TCP showing a broad spectrum of pharmacological activity including antidotal effect in organophosphorus compounds poisoning, radioprotective and anticancer effects. We investigated in vitro interactions of TCP and its adamantane derivative – TAMORF with human erythrocyte acetylcholinesterase (AChE). Moreover, their genotoxicity and radioprotective activity on human white blood cells were studied using the alkaline comet assay, viability testing and the analysis of the structural chromosome aberrations. The tested compounds were found to be weak inhibitors of AChE, for TCP IC 50 = 1 × 10 −5 M and for TAMORF IC 50 > 1 × 10 −3 M, without reactivating and protective effects on AChE inhibited by soman. Results suggest that TCP modified by the replacement of the cyclohexyl ring with an adamantly ring and piperidine with morpholine group (TAMORF) have lower toxicity. Both compounds possess low cytotoxicity and radioprotective activity, but TAMORF also shows cell growth inhibitory effects. To clarify differences in their biological efficiency observed in vitro and in vivo, additional analyses are necessary. Since TAMORF was found to significantly inhibit cell growth and proliferation in vitro, it is reasonably to consider it as a source molecule promising for further modifications and development of more potent substances with antitumor properties rather then radioprotector or antidote in organophosphorus poisoning.