Developing the lead—a chelation bonding theory

Variations were now necessary to see if an analogue could be made which would only bind to the antagonist site. 

The synthesis of the isothiourea (Fig. 13.15) gave a structure where the nitrogen nearest to the imidazole ring was replaced with a sulfur atom. 

The positive charge in this molecule is now restricted to the terminal portion of the chain and should interact more strongly with the proposed antagonist binding site if it is indeed further away. 

Antagonist activity did increase, but the compound was still a partial agonist, showing that binding was still possible to the agonist site. 

The chain was now extended from a two-carbon unit to a three-carbon unit to see what would happen if the guanidine group was moved further away from the imidazole ring. The antagonist activity increased for the guanidine structure (Fig. 13.18), but 

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