Three unreported analogs of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogs of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254) are described, and evaluated for their retinoid-X-receptor (RXR)-selective agonism. Compound 1 has FDA approval as a treatment for cutaneous T-cell lymphoma (CTCL); though, treatment with 1 can elicit side-effects by disrupting other RXR-heterodimer receptor pathways. Of the 7 modeled novel compounds, all analogs stimulate RXR-regulated transcription in mammalian-2-hybrid and RXRE-mediated assays, possess comparable or elevated biological activity based on EC50 profiles, and retain similar or improved apoptotic activity in CTCL assays compared to 1. All novel compounds demonstrate selectivity for RXR and minimal crossover onto the retinoic-acid-receptor (RAR) compared to all-trans-retinoic acid, with select analogs also reducing inhibition of other RXR-dependent pathways (e.g., VDR-RXR). Our results demonstrate that further improvements in biological potency and selectivity of bexarotene can be achieved through rational drug design.

Morphine‐6‐O‐sulfate (M6S) is as a mixed‐action mu/delta (μ/δ) opioid receptor agonist with high potency and analgesic efficacy. These studies used assays of drug discrimination and schedule‐controlled responding to assess abuse‐liability, tolerance, and physical dependence as compared to morphine in rats. Attempts to train 0.3 mg/kg (IP) M6S from saline failed, but all rats rapidly acquired the discrimination when the training dose was changed to 3.0 mg/kg morphine, and substitution tests showed that morphine and fentanyl both fully substituted for the training dose, M6S and M3A6S (3‐O‐acetyl ester of M6S) only partially substituted, and salvinorin A did not elicit morphine‐like effects. Tolerance to response rate‐decreasing effects was studied in rats administered either 1.0 or 3.0 mg/kg morphine or M6S before food‐reinforced operant sessions. At both unit doses, tolerance to M6S‐elicited rate suppression developed more slowly than tolerance to morphine‐induced reductions in response rates. To assess dependence, rats were maintained on 1.0 mg/kg morphine or 1.0 mg/kg M6S until food‐reinforced response rates were stable for at least 5 days. Rats were then administered saline or increasing doses of the opioid antagonist naltrexone (NTX) (0.3, 1.0, 3.0, or 10.0 mg/kg) in order to determine antagonist‐precipitated withdrawal. NTX precipitated withdrawal was similar in both morphine‐maintained and M6S‐maintained rats. In conclusion, the mixed μ/δ agonist activity of M6S failed to completely protect against the development of physical dependence, but delayed tolerance development to behavioral effects and resulted in decreased morphine‐like subjective effects, perhaps implying a decreased abuse liability over μ agonists.