There is considerable interest in the synthesis of K-antagonists as therapeutic agents but also as a means of further understanding the role of the K-opioid receptor. In the search for irreversible and selective reversible K-opioid antagonists, it was decided to modify the structures of the two most well-known K-antagonists, GNTI and norBNI. In particular, two main approaches have been used for the design of novel ligands; these explored the introduction of electrophilic (isothiocyanate) or lipophilic (substituted/unsubstituted benzyl) groups onto the guanidinium moiety of GNTI or at the pyrrolic nitrogen of norBNI. In the first series of compounds, jp-hydroxy-, w-hydroxy-, p-methoxy-, jp-methyland 3,4-dichlorobenzylGNTI analogues have been prepared. Binding and functional studies of /p-hydroxy- and m-hydroxy-derivatives have confirmed the results of molecular modelling studies, which had suggested that the phenolic group of the former should mimic the second phenolic group of norBNI that was previously shown to be crucial for k - antagonist selectivity. Electrophilic ligands modelled on GNTI have also been prepared and N'-(5-isothiocyanatopentyl)GNTI has been sent for biological evaluation, while the successful synthesis of N'-(4-aminobutyl)GNTI will allow the preparation of the corresponding isothiocyanate to be achieved. Modification of norBNI followed previous studies where the duration of action of naltrindole was extended by indolic N-benzylation. In-vivo, BnorBNI was a p-agonist when administered sc and an irreversible K-antagonist when administered icv. This led us to prepare 17,17'-di-NMe derivatives of norBNI and BnorBNI as potential mixed pagonist/K-antagonist ligands. Binding and functional studies of these analogues showed that replacement of the cyclopropyl methyl groups with methyl groups led to a decrease in K-antagonist potency and p-agonist potency with concomitant increase in p-agonist efficacy. We have also prepared isothiocyanates modelled on BnorBNI, with the electrophilic moiety attached directly to the benzyl group of BnorBNI or linked by a methylene spacer. At the time of submission, pharmacological evaluation of these ligands was still outstanding. Finally, unexpected reactions with norBNI have led us to investigate whether the pphthalimidobenzyl group can be used as a general protecting group for indolic and pyrrolic nitrogens. Evaluation on carbazole, tetrahydrocarbazole and an indolomorphinan has shown this is not the case.