Loperamide 1) is a m-opioid receptor (MOR) agonist and it does not easily pass through the blood-brain barrier (BBB). Therefore, it is now mainly used as an antidiarrheal. But recently, it has been reported that when loperamide was administered to a burn on a rat as a peripheal percutaneous cream, it was effective and could not easily pass through the BBB so the manifestion of tolerance did not occur. 2) This report indicates that the peripheral MOR agonists are useful analgesics in the peripheral, especially against inflammatory tissues.In our previous paper, 3) we reported that though our final objective was the synthesis of MOR agonists having peripheral analgesic activity, we intended to synthesize the compounds having more potent activities in two in vitro tests mentioned in the above summary as the first step and then we found compound A accomplishing our purpose (Fig. 1).On the other hand, we had another project. Namely, we intended to synthesize the new MOR agonists having unique structures different from the structure of loperamide. Therefore, we first screened many compounds in our chemical library and then found a seed compound. But, after optimizing the structure, finally we only found the new lead compound 7a(I) which is one of loperamide derivatives. Even so, we continually optimized the structure of 7a(I) in consideration of the structure of A according to the general structure as shown in Chart 1. Then, as a result, we finally found compound 8 having a 10 times more potent MOR agonist activity than loperamide and a potent peripheral analgesic activity in vivo. In this paper, we describe the synthesis of the compounds and their agonist activities on MOR in the guinea-pig ileum. We also describe the affinities to the human MOR, dopioid receptor (DOR) and k-opioid receptor (KOR) expressed in CHO cells of the selected compound 8, and the peripheral analgesic activity of compound 8 in the Randal-Selitto method on rat as an in vivo test.
ChemistryThe 4-hydroxypiperidine derivatives were synthesized as * To whom correspondence should be addressed. New m m-opioid receptor (