Synthesis, structure, in vitro pharmacology, and in vivo activity of trans-3,4-dichloro-N-[[1-(dimethylamino)-4-phenylcyclohexyl]methyl]-benzamide (AP01; 4-phenyl-AH-7921), a novel mixed μ-/κ-opioid

Analogs of non-fentanyl novel synthetic opioids (NSO) with modifications that fall outside of established structure-activity relationships (SARs) for that class of drugs create the question whether or not it should be considered an analog, as defined by 21 U.S.C. 802(32)(A), which is important for its inclusion in the US system of drug scheduling. AH-7921 is a US Schedule I drug and an example of the 1-benzamidomethyl-1-cyclohexyldialkylamine class of NSO. The SARs regarding substitution of the central cyclohexyl ring have not been well characterized in the literature. Therefore, in order to expand the SAR surrounding AH-7921 analogs, trans-3,4-dichloro-N-[[1-(dimethylamino)-4-phenylcyclohexyl]methyl]-benzamide (AP01; 4-phenyl-AH-7921) has been synthesized, analytically characterized, and tested in vitro and in vivo pharmacologically. Using methods described in the original patents for this class of NSO, it was found that the single trans geometric isomer was obtained. The proton nuclear magnetic resonance, mass spectrum, infrared spectrum, and Raman spectrum are reported along with the melting point of the hydrochloride salt. In vitro binding to a battery of 43 central nervous system receptors showed it to be a high-affinity mu-opioid receptor (MOR) and kappa-opioid receptor (KOR) ligand (60 nM and 34 nM, respectively). AP01 also had a 4 nM affinity for the serotonin transporter (SERT), which is a higher level of potency at this receptor than most other opioids. In rats, it exhibited antinociception in the acetic acid writhing test. Therefore, the 4-phenyl modification results in an active NSO, but carries with it potential toxicities beyond those expected for currently approved opioid drugs.

Automated summary

The SARs of substitution of the central cyclohexyl ring in AH-7921 have not been well studied. In order to expand the SARs of AH-7921 analogs, AP01 was synthesized and characterized, and pharmacological tests were conducted. AP01 showed high affinity for μ-opioid receptor (MOR), κ-opioid receptor (KOR), and serotonin transporter (SERT), and exhibited antinociception in rats. However, the 4-phenyl modification in AP01 may lead to potential toxicities beyond currently approved opioid drugs.