New .MU.-Opioid Receptor Agonists with Piperazine Moiety.

Abstract

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...

New .MU.-Opioid Receptor Agonists with Phenoxyacetic Acid Moiety.

“…3) Animals The experiment was performed on male Sprague-Dawley rats weighing 110-150 g (Charles River, Japan). The animals were housed under 12-h light-dark cycle (lights on 7 : 00 a.m.), with room temperature maintained 23Ϯ3°C, and humidity at 50Ϯ20%.…”

“…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).…”

“…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).…”

A Facile Synthesis for Novel Loperamide Analogs as Potential μ Opioid Receptor Agonists

“…Phenylpiperidine structures, such as loperamide ( 1 ) [ 7 , 8 ], N -desmethylloperamide ( 2 ) [ 9 ], diphenoxylate ( 3 ) [ 10 ], and 4 ( Figure 1 ) [ 11 ], are typical representatives of these compounds. Although diphenoxylate and loperamide are MOR agonists and show affinity and selectivity for the cloned μ human opioid receptor, they do not easily pass through the blood–brain barrier (BBB) [ 12 ], therefore, they are currently mainly used as antidiarrheal drugs.…”

Iodine-Mediated One-Pot Synthesis of 2-(Piperazin-1-yl)pyrazine Derivatives from N-Alkyl Piperazines

“…2,3 Also, 2-(piperazin-1-yl)pyrazines are important units in many molecules possessing biological activity. [4][5][6] The presence of this structural motif in many substances of biological significance have led to many approaches being developed to access this chemotype, many of which have been employed in the preparation of pharmaceutical agents. [5][6][7] Molecular iodine, firstly produced from brine in Japan, has been used in organic synthesis for a long time.…”