Recently, it has been reported that morphine, a representative m-opioid receptor (MOR) agonist, showed an analgesic activity in the periphery in mice.1) Additionally it has been recognized that tolerance to the peripheral analgesia was not developed after the repeated administration of morphine in mice.2) Furthermore, it has been reported that the MORs were increased around the inflammatory tissues in animals and humans.3,4) These reports indicate that the MOR agonists are useful analgesics in the periphery, especially against the inflammatory tissues.On the other hand, there are nonsteroidal antiinflammatory drugs (NSAIDs) as peripheral analgesics but they do not have an analgesic efficacy toward some serious peripheral inflammations.5) Therefore, we think that in the serious inflammation cases such as severe burns and grazes, MOR agonists can be effective medicines.As MOR agonists not having the morphinane structures, fentanyl, 6) loperamide 7) and diphenoxylate 8,9) are known. As for fentanyl, to improve the quality of life for cancer patients with pain, the plaster, 10) which has an analgesic activity that lasts for far seventy-two hours, has been developed so the patients do not need to go frequently to the hospital. Although loperamide and diphenoxylate are MOR agonists, they do not easily pass through the blood-brain barrier (BBB). Therefore, they are mainly used as antidiarrheals now.Recently, it has also been reported that when loperamide was administered to a burn on a rat as a peripheral percutaneous cream, it was effective and could not easily pass through the BBB so the manifestation of tolerance did not occur. 11)Therefore, our final objective is the synthesis of MOR agonists having peripheral analgesic activity, and as the first step, we intended to synthesize compounds having more potent activities than loperamide in the two in vitro tests mentioned in the above summary. The three compounds mentioned above have a piperidine moiety in their structures. Currently there is no compound having a piperazine moiety in the structure as a MOR agonist on the market. Therefore, we started to synthesize compounds having a piperazine moiety in their structures. In this paper, we describe the synthesis of the compounds and their affinities to the human MOR and dand k-opioid receptors (DOR and KOR) expressed in CHO cells and their agonist activities on MOR in guinea-pig ileum. ChemistryTo develop our new MOR agonists instead of the already known MOR agonists not having morphinane structures, we thought that our compounds had to have a structural feature. Therefore, based on the knowledge already known, we designed the piperazine (nϭ1) or homopiperazine (nϭ2) derivatives, which have side chains of fentanyl, diphenoxylate and loperamide on a nitrogen with another nitrogen directly connected to various aromatic rings including the heteroaromatic rings.Considering the novelty of our compounds, we first selected the heteroaryl groups as aryl groups. It has been well known that a halogen located in the a-or g-positio...

C4NO3Hs, M= 115.09; orthorhombic, P212t21; a=7.749 (2), b=10.699 (3), c=6.063 (2) A; Z=4, Dm= 1"52 (by flotation), Dx= 1.52 g cm -3. The compound was synthesized from L-alanine and trichloromethyl chloroformate, and crystallized from isopropyl ether at -5°C. The final R value was 0.047 for 681 reflexions. The molecules are linked by weak hydrogen bonds formed between N(1)-H(1) and 0(3') in the b direction.Introduction. The N-carboxy anhydrides (NCA) of amino acids are the most useful monomers for the synthesis of polypeptides. These compounds are generally unstable to moisture and heating. A study has been made on a series of crystal structures of these compounds to explain their polymerizability in the crystalline state. A crystal with the approximate dimensions 0.2×0.4×0.6 mm was mounted on a Rigaku rotating-anode automated four-circle diffractometer, and the intensity data with 20< 55 ° were collected by the usual co-20 scans [8 ° (in 20) min -1] with Zr-filtered Mo K~ radiation. 693 independent reflexions were obtained, 681 of which were regarded as observed. Accurate cell parameters were determined by leastsquares refinements with 26 high-angle reflexions. The structure was solved with MULTAN (Germain, Main & Woolfson, 1970). The non-hydrogen atoms were located on an E map computed with 116 phased re-* Permanent address: . flexions (E> 1.2). When the R (ZllFol-IFclIlYlFol) value dropped to 0.13 by block-diagonal least-squares refinement, a difference Fourier map revealed all the H atoms. The weights were 0.5 for unobserved reflexions 1.3 5 Ha

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 (

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