Cooperative reinforcement of opioid pharmacophores

In recent years several opioid receptors have been characterized (mu, kappa, delta, et cetera); furthermore, it has been suggested that different receptor types mediate different neurophysiological responses. It has also been found that there exist endogenous opioid peptides which reveal some selectivity for a particular receptor type. These observations created a need for selective agonists and antagonists of a particular receptor type, and indicated a possibility of developing selective opioid drugs with reduced side effects. All endogenous peptides have an identical N-terminal part, which suggests that opioid receptor pockets in the message part are similar or identical. The main elements which differentiate the selectivity of endogenous peptides are surroundings of receptor pockets, different organization of opioid receptors and their interactions with other receptors and enzymatic systems. This opens a possibility of successful modifications of biochemical and/or physiological properties of opioid pharmacophores through modification of the elements which could be connected with the opioid message. Depending on the character of the connecting element, the pharmacophores may be divided into three main types: (i) opioid pharmacophores coordinated with the address; (ii) bivalent opioids; (iii) bifunctional pharmacophores.