Studies on 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives and their analgesic activities. 2. Structure-activity relationships of 1-cycloalkyl-4-(1,2-diphenylethyl)piperazines

Natsuka, Kagayaki; Nakamura, Hideo; Negoro, Toshiyuki; Uno, Hitoshi; Nishimura, Haruki

doi:10.1021/jm00210a017

Cited by 19 publications

(5 citation statements)

References 5 publications

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“…A more recent example of this approach may be found in the 1,2-diarylethylamine class which gives rise to a range of substances with diverse properties and may include examples such as MT-45 (analgesic activity in mice and also sold as a 'research chemical') [10,11] and AZD6765 (potential antidepressant properties in humans) [12] (Figure 1). A relatively new addition to the product catalog of online retailers is diphenidine (1) (1-(1,2-diphenylethyl) piperidine, 1,2-DEP) ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Preparation and characterization of the ‘research chemical’ diphenidine, its pyrrolidine analogue, and their 2,2‐diphenylethyl isomers

Wallach

Kavanagh

McLaughlin

et al. 2014

Drug Testing and Analysis

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Substances with the diphenylethylamine nucleus represent a recent addition to the product catalog of dissociative agents sold as ‘research chemicals’ on the Internet. Diphenidine, i.e. 1‐(1,2‐diphenylethyl)piperidine (1,2‐DEP), is such an example but detailed analytical data are less abundant. The present study describes the synthesis of diphenidine and its most obvious isomer, 1‐(2,2‐diphenylethyl)piperidine (2,2‐DEP), in order to assess the ability to differentiate between them. Preparation and characterization were also extended to the two corresponding pyrrolidine analogues 1‐(1,2‐diphenylethyl)‐ and 1‐(2,2‐diphenylethyl)pyrrolidine, respectively. Analytical characterizations included high‐resolution electrospray mass spectrometry (HR‐ESI‐MS), liquid chromatography ESI‐MS/MS, gas chromatography ion trap electron and chemical ionization MS, nuclear magnetic resonance spectroscopy (NMR) and infrared spectroscopy. Differentiation between the two isomeric pairs was possible under GC‐(EI/CI)‐MS conditions and included the formation of distinct iminium ions, such as m/z 174 for 1,2‐DEP and m/z 98 for 2,2‐DEP, respectively. The pyrrolidine counterparts demonstrated similar phenomena including the expected mass difference of 14 Da due to the lack of one methylene unit in the ring. Two samples obtained from an Internet vendor provided confirmation that diphenidine was present in both samples, concurring with the product label. Finally, it was confirmed that diphenidine (30 μM) reduced N‐methyl‐D‐aspartate‐mediated field excitatory postsynaptic potentials (NMDA‐fEPSPs) to a similar extent to that of ketamine (30 μM) when using rat hippocampal slices. The appearance of 1,2‐ diphenylethylamines appears to reflect the exploration of alternatives to arylcyclohexylamine‐type substances, such as methoxetamine, PCP and PCPy‐based analogues that also show NMDA receptor activity as demonstrated here for diphenidine. Copyright © 2014 John Wiley & Sons, Ltd.

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Section: Introductionmentioning

confidence: 99%

Preparation and characterization of the ‘research chemical’ diphenidine, its pyrrolidine analogue, and their 2,2‐diphenylethyl isomers

Wallach

Kavanagh

McLaughlin

et al. 2014

Drug Testing and Analysis

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“…More recently, AH-7941 appeared in the United States, the United Kingdom, Sweden, Norway, and Japan resulting in toxicities and overdoses (EMCDDA, 2014b;Kronstrand et al, 2014;Rambaran et al, 2018). Similarly, 2diphenylethyl) piperazine) was initially developed and later abandoned by Dainippon Pharmaceutical Company in Japan as an alternate analgesic chemically distinct from other opioids (Natsuka et al, 1978;Natsuka et al, 1987). MT-45 also has appeared in illicit global drug markets resulting in toxicities and overdoses (EMCDDA, 2014a;Fels et al, 2017;Solimini et al, 2018) The use of a competitive antagonist is a key component to pharmacologically characterize novel compounds.…”

Section: Downloaded Frommentioning

confidence: 99%

Antinociceptive and Discriminative Stimulus Effects of Six Novel Psychoactive Opioid Substances in Male Rats

Walker

Chambers

Korber

et al. 2021

J Pharmacol Exp Ther

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Compounds with novel or fentanyl-like structures continue to appear on the illicit drug market and have been responsible for fatalities, yet there are limited preclinical pharmacological data available to evaluate the risk of these compounds to public health. The purpose of the present study was to examine acetyl fentanyl, butyryl fentanyl, AH-7921, MT-45, W-15, and W-18 for their relative potency to reference opioids and their susceptibility to naltrexone antagonism using the 55 o C warm-water, tail-withdrawal assay of antinociception and a morphine drug discrimination assay in male, Sprague Dawley rats. In the antinociception assay, groups of 8 rats per drug were placed into restraining tubes, their tails were immersed into 40 o or 55 o C water, and the latency for tail withdrawal was measured with a cutoff time of 15 sec. In the drug discrimination assay, rats (n=11) were trained to discriminate between 3.2 mg/kg morphine and saline, s.c., in a two-choice, drug discrimination procedure under a fixed ratio-5 schedule of sucrose pellet delivery. Morphine, fentanyl, and four of the synthetic opioids dose-dependently produced antinociception and fully substituted for morphine in the drug discrimination assay with the following rank order of potency: fentanyl>butyryl fentanyl>acetyl fentanyl>AH-7921>MT45>morphine. All drugs that produced antinociception or morphine-like discriminative stimulus effects were blocked by naltrexone. W-15 and W-18 did not show antinociceptive or morphine-like discriminative stimulus effects at the doses tested supporting a lack of opioid activity for these two compounds. These findings suggest that butyryl fentanyl, acetyl fentanyl, AH-7941, and MT-45 have abuse liability like other opioid agonists.

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“…The overall goal for pharmaceutical companies when designing new opioids is to create an effective analgesic drug that does not have any of the negative side effects of currently manufactured opioids. Many synthetic opioids currently being Natsuka et al (1978) seen on the market were actually synthesized and scheduled in the 1970s and 1980s. In order to understand the driving force behind this, an understanding of opioid pharmacology is important.…”

Section: Opioid Pharmacologymentioning

confidence: 99%

A toxicological exploration of the opioid crisis

Krug

Scott

2020

WIREs Forensic Science

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With the discovery of opium dating back to Ancient Greek and Ancient Egyptian civilizations, there is a rich history stemming from the early use of the poppy plant to the new synthetic opioids that are emerging in drug seizures today. The phrase "opioid crisis" has been used to describe a public health emergency that has developed due to a combination of the over-prescription of opioid medication, increase in heroin use, and clandestine synthesis of

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Studies on 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives and their analgesic activities. 2. Structure-activity relationships of 1-cycloalkyl-4-(1,2-diphenylethyl)piperazines

Cited by 19 publications

References 5 publications

Preparation and characterization of the ‘research chemical’ diphenidine, its pyrrolidine analogue, and their 2,2‐diphenylethyl isomers

Preparation and characterization of the ‘research chemical’ diphenidine, its pyrrolidine analogue, and their 2,2‐diphenylethyl isomers

Antinociceptive and Discriminative Stimulus Effects of Six Novel Psychoactive Opioid Substances in Male Rats

A toxicological exploration of the opioid crisis

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