Inhibition of hMDR-1 as a cell model for blood-brain barrier transmission
An in vitro cell culture system tested the efficacy of selective Dmt-Tic analogues to interact with the transmembrane protein pump used to detoxify cells, human multidrug resistance P-glycoprotein-1. Several analogues, in the series N,N-(CH3)-Dmt-Tic-NH-1-adamantane, H-Dmt-Tic-NH-1-adamantane, N,N-(CH3)-Dmt-Tic-NH-tert-butyl > H-Dmt-Tic-Ala- NH-1-adamantane > H-Dmt-Tic-NH-tert-butyl > cyclo(Dmt-Tic) competed with effectively in parallel to the standard drug verapamil. A large number of other analogues and opioid peptides and opiates for δ- or µ-opioid receptors were inactive.
Centrally mediated analgesia by unique μ-opioid receptor agonists
Intracerebroventricular (icv) administration established that the compounds acted centrally. Using mice with the tail-flick (spinal) and hot-plate (supraspinal) tests in comparison morphine and deltorphin C for µ- and δ-opioid receptors, respectively, the results clearly established that 1,4-bis-[Dmt-NH]-butane1 and 3-(4'-Dmt-aminobutyl)-6-(3'-Dmt-aminopropyl)-5-methyl-2(1H)-pyrazinone acted within the brain. In fact, the later compound was far more potent than morphine, and about 30-fold more potent than the alkyl derivatives. This effect was blocked by naloxone, a nonspecific opiate antagonist.
Pharmacological differentiation of antinociception by μ-opioid receptor subtypes
Considering that two pharmacologically active µ-opioid receptor sites are known, µ1 and µ2, the application of specific opiate inhibitors (δ-funaltrexamine, an irreversible inhibitor of µ1 and µ2 subtypes; naloxanozine, µ1 subtypes), as well as naltrindole (δ-opiate antagonist), determined which receptor form was responsible for spinal or supraspinal effects. Naltrindole partially blocked spinal-induced analgesia (47%) and completely inactive toward supraspinal analgesia. Thus, spinal effects involved µ1-, µ2- and δ-opioid receptors, while supraspinal analgesia indicated a preference for only µ1-opioid receptors.
Peripheral-induced analgesia mediated through µ-opioid receptors
The peripheral induced analgesia by 1,4-bis-[Dmt-NH]-butane and 3-(4'-Dmt-aminobutyl)-6-(3'-Dmt-aminopropyl)-5-methyl-2(1H)-pyrazinone was verified by subcutaneous (sc) injection. The former was about 10-12% as active as morphine, while the latter was approximately half. Thus, these compounds were readily transported to and crossed the blood-brain barrier (BBB) to interact with µ-opioid receptors. Similar values were obtained with 3,6-bis-(3'-Dmt-aminopropyl)-5-methyl-2(1H)-pyrazinone.
Oral bioavailability of a Dmt-pyrazinone derivative for CNS analgesia
The symmetric Dmt-containing opioidmimetic, 3,6-bis-(3'-Dmt-aminopropyl)-5-methyl-2(1H)-pyrazinone, which had potent CNS analgesic properties, was active by sc injection and oral administration. The effect is substantially greater than other non-modified opioids or a prodrug.
The symmetric Dmt-containing opioidmimetic, 3,6-bis-(3'-Dmt-aminopropyl)-5-methyl-2(1H)-pyrazinone, which had potent CNS analgesic properties, was active by sc injection and oral administration. The effect is substantially greater than other non-modified opioids or a prodrug.
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