For psychomodulators, some fragments in the chemical structures will play a decisive role in the regulation of certain key physiological indicators [1]. The changes in these physiological indicators may alter the neurochemical or behavioral effects [2]. For example, addition of a methylenedioxy moiety to prototype monoamine transporter substrate amphetamine (3,4-methylenedioxyamphetamine; MDA) can directly attenuated the dopamine (DA) versus serotonin (5-HT) selectivity to increase extracellular monoamine levels [3]. Changes in these substituents not only differentially impact the discriminative stimulus effects of monoamine transporter substrates, but also have a certain constraint on its addiction properties [3]. Data from both humans and animals suggested that regular 3,4-methylenedioxymethamphetamine (MDMA, methylenedioxy addition on the cocaine-like effects of methamphetamine) produced adaptations in the DA and 5-HT systems that were associated with substance use disorder and related behaviors, such as increased impulsivity [4,5].

Compounds with methylenedioxy analogs, such as natural and synthetic aporphines (Fig. 1) have emerged as a new class of monoamine transporter substrates [[6], [7], [8]]. There are a number of aporphines reported as ligands of DA and 5-HT receptors [7,8]. They have clear potential for central nervous system (CNS) interventions, but there are selective differences in the regulation of related receptors, which may be related to the variety of substituents [6]. Early structure-activity relationship (SAR) studies mainly focused on the optimization of apomorphine for improving pharmacokinetic profiles, potency, and subtype selectivity [8,9]. However, whether such psychotropic substances produce differential behavioral effects (for example, antidepressant activity and addictive properties) from their most common methylenedioxy analog counterparts has not been systematically examined. The lack of such research undoubtedly leads to a lack of clear direction in the design of subsequent compounds, resulting in wasting too much time on the selection of other substituents.

Given the potential for receptors target differences noted above for aporphines, the aim of this study was to directly compare the effects and addictive potential of methylenedioxy open-loop and closed-loop aporphines on the performance in terms of antidepressant efficacy. The results may provide a reference for the design of this class of psychotropic substances in the follow-up CNS modulation drugs.