I. In vivo evidence for partial agonist effects of (−)-OSU6162 and (+)-OSU6162 on 5-HT2A serotonin receptors

Abstract

The locomotor effects of (-)- and (+)-OSU6162 were evaluated in 'low activity' animals (reserpinized mice and habituated rats) and 'high activity' animals (drug-naive mice and non-habituated rats). Both enantiomers of OSU6162 had dual effects on behavior, stimulating locomotor activity in 'low activity' animals and inhibiting locomotor activity in 'high activity' animals. There were also certain differences between the two enantiomers in their behavioral profiles. The stimulatory effects of both enantiomers in reserpinized mice were blocked by the 5-HT2A selective antagonist M100907, but not by the D2-selective antagonists haloperidol or raclopride, or by the D1-selective antagonists SCH23390 or SCH39166. The stimulatory effect in mice was more pronounced for (+)- than for (-)-OSU6162. In drug-naive mice, both enantiomers of OSU6162 produced head twitches, albeit to a much lesser extent than DOI, and both enantiomers inhibited DOI-induced head twitches, the (-)-form more effectively so than the (+)-form. These results suggest that (-)- and (+)-OSU6162 are partial agonists on 5-HT2A receptors and that the (+)-form has a higher intrinsic activity than the (-)-form. At high doses, both enantiomers inhibited locomotor activity in drug-naive mice, with (-)-OSU6162 being more potent than (+)-OSU6162. Similarly, in high-active rats, both enantiomers inhibited locomotor activity, with the (-)-enantiomer being more potent than the (+)-enantiomer. Conversely, in habituated rats, both enantiomers stimulated locomotor activity, and here, as opposed to the case in low-active mice, (-)-OSU6162 was more effective than (+)-OSU6162. The stimulatory effects in habituated rats of both enantiomers could be antagonized with either haloperidol or M100907. Overall, these results indicate that the dual effects on behavior of (-)- and (+)-OSU6162 are mediated through D2 and 5-HT2A receptors, consistent with their in vitro functional selectivity profiles (see Burstein et al., accompanying paper). Thus, both enantiomers of OSU6162 seem to act as stabilizers not only on dopaminergic, but also on serotonergic brain signaling. These discoveries have important implications for the potential clinical utility of both compounds, as well as for several of their congeners.

Recent advances in the neuropsychopharmacology of serotonergic hallucinogens

“…Phenylalkylamines, including DOI, mescaline, and TCB-2, inhibit investigatory behavior and alter locomotor activity in a dose-dependent manner, increasing activity at low to moderate doses and reducing activity at high doses (Halberstadt et al, 2009, 2013). Other groups have reported similar findings with DOM and DOI in mice (Yamamoto and Ueki, 1975; Darmani, 1996; Brookshire and Jones, 2009; Carlsson et al, 2011). The increase in locomotor activity induced by 1 mg/kg DOI, 25 mg/kg mescaline, or 3 mg/kg TCB-2 is blocked by low doses of M100907 and is absent in 5-HT 2A knockout mice.…”

Head‐twitch response in rodents induced by the hallucinogen 2,5‐dimethoxy‐4‐iodoamphetamine: a comprehensive history, a re‐evaluation of mechanisms, and its utility as a model

“…Finally, it is noteworthy that novel, partial 5-HT 2A /D 2 receptor agonists also attenuate the DOI-elicited HTR. [235,236] These observations provide further support for the idea that DOI potentially stabilizes a 5-HT 2A receptor conformation unique from other 5-HT 2A receptor agonists. It would be interesting to know whether pre-treatment with LSD or DOM attenuates the DOI-induced HTR, as the outcome could potentially strengthen the argument for ligand-specific receptor conformations.…”

Tolerability and efficacy of the monoaminergic stabilizer (−)-OSU6162 (PNU-96391A) in Huntington’s disease: a double-blind cross-over study

“…These agents, called (− )-OSU6162 and pridopidine, respectively, have been shown to act on both dopaminergic and serotonergic receptor subpopulations in such a way as to enable them to both stimulate and inhibit behaviour, depending on whether the baseline level is low or high, respectively (4)(5)(6). In an early small open study ( − )-OSU6162 was given as single intravenous doses to HD patients, and a reduction of choreatic symptoms was noted (7, and unpublished data).…”