Identifying nonaddictive opioid medications is a high priority in medical science, but μ-opioid receptors (MORs) mediate both the analgesic and addictive effects of opioids. We found a significant pharmacodynamic difference between morphine and methadone that is determined entirely by heteromerization of MORs with galanin Gal1 receptors (Gal1Rs), rendering a profound decrease in the potency of methadone. This finding was explained by the weaker proficiency of methadone in activating the dopaminergic system as compared with morphine and predicted a dissociation of the therapeutic and euphoric effects of methadone, which was corroborated by a significantly lower incidence of self-reports of feeling “high” in methadone-medicated patients. These results suggest that μ-opioid–Gal1R heteromers mediate the dopaminergic effects of opioids. The results further suggest a lower addictive liability of some opioids, such as methadone, due to their selective low potency for the μ-opioid–Gal1R heteromer.

Enantiomeric N-phenethyl-m-hydroxyphenylmorphans with various substituents in the ortho, meta or para positions of the aromatic ring in the phenethylamine side-chain (chloro, hydroxy, methoxy, nitro, methyl), as well as a pyridylethyl and a indolylethyl moiety on the nitrogen atom, were synthesized and their binding affinity to the µ-, δ-, and κ-opioid receptors was examined. The higher affinity ligands were further examined in the [³⁵S]GTPγS assay to study their function and efficacy. 3-((1R,5S)-(−)-2-(4-Nitrophenethyl)-2-aza-bicyclo[3.3.1]nonan-5-yl)phenol ((−)-10m) was found to be a µ-agonist and δ-antagonist in that functional assay and was about 50 fold more potent than morphine in vivo. 3-((1R,5S)-(−)-2-(4-Chlorophenethyl)-2-aza-bicyclo[3.3.1]nonan-5-yl)phenol ((−)-10i) and several other ligands displayed inverse agonist activity at the δ-opioid receptor. The absolute configuration of all of the reported compounds was established by chemical conversion of (−)-6 to 1R,5S-(−)-8b·HBr.

Prior work indicated that serotonin transporter (SERT) inhibitors competitively inhibit substrate‐induced [³H]5‐HT release, producing rightward shifts in the substrate‐dose response curve and increasing the EC₅₀ value without altering the E_max. We hypothesized that this finding would not generalize across a number of SERT inhibitors and substrates, and that the functional dissociation constant (Ke) of a given SERT inhibitor would not be the same for all tested substrates. To test this hypothesis, we utilized a well‐characterized [³H]5‐HT release assay that measures the ability of a SERT substrate to release preloaded [³H]5‐HT from rat brain synaptosomes. Dose‐response curves were generated for six substrates (PAL‐287 [naphthylisopropylamine], (+)‐fenfluramine, (+)‐norfenfluramine, mCPP [meta‐chlorophenylpiperazine], (±)‐MDMA, 5‐HT) in the absence and presence of a fixed concentration of three SERT inhibitors (indatraline, BW723C86, EG‐1‐149 [4‐(2‐(benzhydryloxy)ethyl)‐1‐(4‐bromobenzyl)piperidine oxalate]). Consistent with simple competitive inhibition, all SERT inhibitors increased the EC₅₀ value of all substrates. However, in many cases a SERT inhibitor decreased the E_max value as well, indicating that in the presence of the SERT inhibitor the substrate became a partial releaser. Moreover, the Ke values of a given SERT inhibitor differed among the six SERT substrates, indicating that each inhibitor/substrate combination had a unique interaction with the transporter. Viewed collectively, these findings suggest that it may be possible to design SERT inhibitors that differentially regulate SERT function. Synapse 64:862–869, 2010.

All possible diastereomeric C9-hydroxymethyl-, hydroxyethyl-, and hydroxypropyl-substituted 5-phenylmorphans were synthesized to explore the three-dimensional space around the C9 substituent in our search for potent MOR partial agonists. These compounds were designed to lessen the lipophilicity observed with their C9-alkenyl substituted relatives. Many of the 12 diastereomers that were obtained were found to have nanomolar or subnanomolar potency in the forskolin-induced cAMP accumulation assay. Almost all these potent compounds were fully efficacious, and three of those chosen for in vivo evaluation, 15, 21, and 36, were all extremely G-protein biased; none of the three compounds recruited beta-arrestin2. Only one of the 12 diastereomers, 21 (3-((1S,5R,9R)-9-(2-hydroxyethyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), was a MOR partial agonist with good, but not full, efficacy (E_max = 85%) and subnanomolar potency (EC₅₀ = 0.91 nM) in the cAMP assay. It did not have any KOR agonist activity. This compound was unlike morphine in that it had a limited ventilatory effect in vivo. The activity of 21 could be related to one or more of three well-known theories that attempt to predict a dissociation of the desired analgesia from the undesirable opioid-like side-effects associated with clinically used opioids. In accordance with the theories, 21 was a potent MOR partial agonist, it was highly G-protein biased and did not attract beta-arrestin2, and it was found to have both MOR and DOR agonist activity. All the other diastereomers that were synthesized were either much less potent than 21 or had either too little or too much efficacy for our purposes. It was also noted that a C9-methoxymethyl compound with 1R,5S,9R stereochemistry (41) was more potent than the comparable C9-hydroxymethyl compound 11 (EC₅₀ = 0.65 nM for 41 vs. 2.05 nM for 11). Both 41 and 11 were fully efficacious.