Abstract
In the last decade, much interest has been shown in the development of agonists selective for the κ‐opioid receptor, which are potentially useful as analgesics with fewer side effects than morphine. The prototype drug is the benzeneacetamide U 50488, which was used in the present study as a starting point for molecular modelling of newer congeners. The heat of formation corresponding to the recently reported crystal structure of U 50488 was minimized with the semi‐empirical molecular orbital program MOPAC. Similar minimization and subsequent superimposition of all compounds used in the study yielded a template that was used for further discussion and manipulation. From the template, it appeared that compounds conformationally less restrained than U 50488, such as ICI 199441, may better accommodate the receptor environment. In addition, the template was used to generate ideas for the design of novel compounds. Finally, the little resemblance of the template to older, only marginally selective compounds, such as ethylketocyclazocine and the endogenous peptide dynorphin, supports the biochemical/pharmacological hypothesis of the existence of different subtypes of κ‐opioid receptors.