A simple and general synthesis of vanillamides was developed and employed to screen acids from the fatty and isoprenoid pools for new acyl templates of biological relevance as capsaicin analogues. Potent activation of the human vanilloid receptor 1 (VR1) was observed for the vanillamides of certain polyfunctional acids from both pools, showing that the vanilloid activity of capsaicinoids can be substantially improved by introducing polar groups and/or unsaturations on the acyl moiety. The activity of the unsaturated analogues was maintained or even increased by cyclopropanation, while omega dimerization led to a substantial increase of activity. Because of the wide structural diversity of the library of compounds screened, these observations could not be translated into a single framework of structure-activity relationships. Nevertheless, a series of new highly active leads was identified, validating the pharmacological potential of the unnatural combination of natural building blocks to provide new bioactive compounds.