Danuta Kunce

Influence of new deltorphin analogues on reinstatement of cocaine-induced conditioned place preference in rats.

The aim of this study was to investigate whether the δ-opioid receptors are involved in the rewarding and reinstatement effect of cocaine in the conditioned place preference (CPP) test. Male Wistar rats were conditioned with cocaine (5 mg/kg) or saline in a biased CPP procedure. The intracerebroventricular (i.c.v.) administration of naltrindole (5 nmol), δ-opioid receptor antagonist but not β-funaltrexamine (5 nmol), or nor-binaltorphimine (10 nmol), μ-opioid and κ-opioid receptor antagonists, respectively reversed the expression of the cocaine CPP. The i.c.v. administration of new analogues of deltorphins with potent agonist activity at δ-opioid receptors, such as cyclo(Nδ, Nδ-carbonyl-D-Orn2, Orn4)deltorphin (DEL-6) at the dose of 10 and 20 nmol and deltorphin II N-(ureidoethyl)amide (DK-4) at the dose of 10 and 20 nmol reinstated the rewarding effect of cocaine after extinction sessions in the CPP test. Naltrindole (5 nmol, i.c.v.) abolished the reinstated effect of DK-4 (10 nmol). In addition, DEL-6 and DK-4 induce anxiolytic-like effects in the elevated plus-maze test. However, neither peptide given alone either produced a rewarding effect in the CPP test, or influenced the locomotor activity and motor coordination, thus suggesting that these effects of peptides did not influence the results obtained in the reinstatement procedure of CPP. In conclusion, our results show that δ-opioid receptors play a dominant role in cocaine reward and reinstatement of cocaine seeking behavior in the CPP test.

Evaluation of Carbodiimides Using a Competition Method

A competitive reaction of activated Boc‐Ala‐OH and Boc‐Phe‐OH with H‐Leu‐resin has been developed for assessing the relative efficiencies of different carbodiimides. This allowed a comparison of the efficiency of the carbodiimides N,N;′‐dicyclohexylcarbodiimide,N,N′‐diisopropylcarbodiimide, N‐tert‐butyl‐N′‐methylcarbodiimide and N‐tert‐butyl‐N′‐ethylcarbodiimide. Comparable results were obtained when these reagents were used for the preformation of symmetrical anhydrides or of 1‐hydroxybenzotriazole esters in situ. Differential incorporation was observed when asymmetrical carbodiimides were used for peptide bond formation by the direct carbodiimide procedure.

Synthesis of peptidomimetics: An evaluation of the p-nitrophenyl carbamate of ethylenediamine

The application of p-nitrophenyl carbamate of Boc-ethylenediamine forthe solid-phase synthesis of peptidomimetics was examined. The per step yield of coupling was estimated using mass spectrometry, based on the repeated coupling of the same monomer in the synthesis of alkylurea oligomers. Introduction of the urea moiety at the terminus of the chain adjacent to the resin was accomplished by the use of the BHA resin in the assembly of the chain and liquid HF in the cleavage step. In addition, an alkylurea oligomer was treated with bis(p-nitrophenyl) carbonate followed by ammonolysis in order to obtain a urea moiety at the terminus distant from the resin. Aside from the expected oligomer, a product was obtained in which the terminal alkylurea had undergone cyclization. Finally, four peptidomimetics, analogues of 1–4 enkephalin fragment, containing up to four alkylurea units instead of glycine residues, were synthesized. Two of these peptidomimetics were examined for opioid activity and turned out to be active in the guinea pig ileum assay.