AH-7921 was designed, synthesized, developed, and patented in the mid 1970s by researchers from the University of Aston (Birmingham) and the pharmaceutical company Allen and Hanburys Ltd. It was synthesized among other N-substituted cyclohexylmethylbenzamide derivatives as a potential analgesic agent due to its structural similarity to fentanyl and phencyclidine (Fig. 1). AH-7921 proved to be the most active compound of the designed series in animal models tested possessing significant analgesic properties (ED 50 = 0.55 mg/kg). Especially in mouse, AH-7921 showed an analgesic action equal to morphine (ED 50 = 0.45 mg/kg) when inhibiting phenylquinone-induced writhing [8]. After subcutaneous administration in mice, the drug proved to be an antinociceptive agent during hot-plate test [19].

Because early in vivo animal studies of AH-7921 revealed its potent analgesic activity, it was selected among the series of N-substituted cyclohexylmethylbenzamides for further investigation and detailed studies in higher species. Particularly, orally administered doses of AH-7921 in conscious dogs led to suppression of pain response (to electrical stimulation of the dental pulp) to an extent similar to that of morphine with a minimal effective antinociceptive oral dose of 1.25 mg/kg. The corresponding analgesic dose for codeine was 3.5 mg/kg. In rhesus monkeys, the minimal oral antinociceptive (for similarly induced pain) doses of AH-7921, codeine, and morphine were 13.8, 11.3, and ≤5.0 mg/kg, respectively. These doses caused no overt behavioral effects in the above examined animal models, although higher oral doses of 50 mg/kg caused slight central nervous system depression. Further studies by the same scientific group of Allen and Hanburys Ltd. revealed the addictive liability of AH-7921; administration of naloxone to rats that were orally treated with 5 mg AH-7921/kg three times daily that increased to 20 mg AH-7921/kg three times daily over 5 days caused an withdrawal syndrome similar to that produced in animals that had received morphine on a similar dosage schedule. The symptoms were completely alleviated after administration of certain doses of AH-7921. In addition, on terminating AH-7921 treatment, withdrawal signs appeared over a period of 24–48 h, which indicates that the physical dependence produced is similar to that of opioids [20].

Sewell and Spencer [21] in their study showed that the antinociceptive effects of subcutaneously injected morphine or AH-7921 were prolonged in both cases by intracerebroventricularly injecting serotonin in mice, while noradrenaline attenuated the antinociceptive effects of these two analgesics. Thus, it was assumed that AH-7921 interacts in vivo with brain-penetrating serotonergic and adrenergic drugs.

More recent studies in rodents indicated that AH-7921 was a μ-opioid receptor agonist, while κ-opioid receptors were also involved to its analgesic effect against chemically induced pain [19]. This moderate selectivity towards μ- over κ-opioid receptors was also confirmed in vitro using opioid receptor preparations from guinea pig brains [22]. Hayes and Tyers [8] studied the antinociceptive effects, as well as the adverse effects produced by AH-7921 and other selected opioid receptor agonists, after subcutaneous administration in mice. These adverse effects included miosis, Straub tail response, hypothermia, sedation, respiratory depression (ED 50 = 2.5 mg/kg), and inhibition of gastrointestinal propulsion. In general, these effects of AH-7921 were similar to those of morphine, indicating a shared mode of action at the receptor level, while they were significantly reduced by simultaneous subcutaneous administration of naloxone. These results demonstrated that the doses that produced side effects were close to those responsible for its analgesic action. In the same study, morphine was found to have a twofold greater safety margin than AH-7921, which suggests easier appearance of toxic effects after AH-7921 use [8].

There are no published studies concerning the pharmacological or toxicological action of AH-7921 in humans and the clinical features of its acute toxicity [7]. Most of that information comes from drug users. Thus, the only available information related to the use and the effects of this drug is scarce and originates from Internet drug forums and a limited number of recently published poisoning cases. AH-7921 as a μ-opioid receptor agonist produces relaxation, euphoria, respiratory depression, nausea, hypertension, and hypothermia, as users of this drug have mentioned [6, 10]. However, it is difficult to estimate the role of κ-opioid receptor agonism in the overall physiological and psychological effects of AH-7921 in humans. Drug users reported that the desired (positive) effects of AH-7921 after oral intake include physical anesthetic effect, euphoria, mental relaxation, and pleasant mood lift, while nausea and vertigo induced by movement appeared as adverse (negative) effects that could be minimized by having a meal 2–4 h prior to ingestion. According to a user who had been in search of a substance that would provide pain management and tried AH-7921 orally, “The effects of AH-7921 seem to be highly predictable and repeatable. Nearly every experience exhibited the same basic effects on my mental and physical being. I found the intensity of the effects to correspond in a linear relationship to the dosage amount” [17].

An AH-7921 user mentioned that the inhalation of vapors in an amount of 40 mg as free base led to a very relaxing and pleasant experience, euphoria, and pain relief similar to those produced by doses of morphine as low as 10 mg. The peak-effects lasted for 1.5 h. No other effects except warmness of body, extreme relaxation, analgesic effects, medium euphoria, and miosis (occurring with the use of other opioids) were noticed [16]. Two AH-7921 users experienced similar effects as well as an addition “opiate glow”, alertness, occasional itching, nausea, and tremors after sublingual administration and re-dosing of a solution of powder AH-7921 in lemon juice and warm water [23]. No serious adverse effects were observed by these users.

A user who consumed orally in total 2 g of AH-7921 in 3 weeks experienced feelings of depression and mild insomnia after withdrawal from the drug, while his second experience resulted in a visit to hospital with “numbness, spasms, and twitches” [18]. Other users have confirmed that AH-7921 can lead to withdrawal symptoms worse than morphine due to its much longer half-life [24].