Functional Selectivity and Partial Efficacy at the Monoamine Transporters: A Unified Model of Allosteric Modulation and Amphetamine-Induced Substrate Release

Abstract

All clinically approved drugs targeting the plasmalemmal transporters for dopamine, norepinephrine, and serotonin act either as competitive uptake inhibitors or as amphetamine-like releasers. Monoamine transporter (MAT) ligands that allosterically affect MAT-mediated substrate uptake, release, or both were recently discovered. Their modes of action have not yet been explained in a unified framework. Here, we go beyond competitive inhibitors and classic amphetamines and introduce concepts for partial efficacy at and allosteric modulation of MATs. After we elaborate on a kinetic account for amphetamine action, we provide an explanation for partial release (i.e., the observation that some amphetamines are less efficacious than others in inducing monoamine efflux). We then elucidate mechanisms of allosteric inhibition and stimulation of MATs, which can be functionally selective for either substrate uptake or amphetamineinduced release. These concepts are integrated into a parsimonious kinetic framework, which relies exclusively on physiologic transport modes (without any deviation from an alternating access mechanism). The model posits cooperative substrate and Na 1 binding and functional selectivity by conformational selection (i.e., preference of the allosteric modulators for the substrate-loaded or substrate-free states of the transporter). Thus, current knowledge about the kinetics of monoamine transport is sufficiently detailed to provide a quantitative description of the releasing action of amphetamines, of substrate uptake, and of selective modulation thereof by allosteric modulators.

How to rescue misfolded SERT, DAT and NET: targeting conformational intermediates with atypical inhibitors and partial releasers

“…It has also been appreciated that amphetamine-like releasers differ in their efficacy; the term partial releaser was coined to differentiate the compounds with reduced ability to trigger the substrate-exchange mode from those, which cause maximum efflux of monoamines [19,67]. Partial releasers trap the transporter in intermediate conformations (Figure 5, right), which must be transited during the transport cycle [19].…”

“…It has also been appreciated that amphetamine-like releasers differ in their efficacy; the term partial releaser was coined to differentiate the compounds with reduced ability to trigger the substrate-exchange mode from those, which cause maximum efflux of monoamines [19,67]. Partial releasers trap the transporter in intermediate conformations (Figure 5, right), which must be transited during the transport cycle [19]. In fact, there appears to be a continuum between substrates, releasers and inhibitors: this conjecture is supported by the following observations: (i) cathinone is a releaser [16], but bupropion, a derivative of cathinone is an atypical inhibitor, (ii) 3,4-methylenedioxy-N,N-dimethylamphetamine (MDDMA) is a partial releaser, which can also adopt an inhibitory binding mode, its analogue 3,4-methylenedioxy-N,N,N-trimethylamphetamine (MDTMA) only binds in the inhibitory mode [77].…”

“…These can be either positive or negative allosteric modulators [84,85]. Their selective action on amphetamine-induced reverse transport can be rationalised by kinetic modelling; they are predicted to stabilise the inward-open apo- and/or substrate-bound states of monoamine transporters [19]. Thus, allosteric modulators are not only candidate compounds for the treatment of addiction [67] but they may also be effective pharmacochaperones.…”

“…Furthermore, it has been appreciated that another class of compounds differ from typical releasers in their efficacy. Because they induce less release than amphetamine and other full releasers, they are referred to as partial releasers [19]. Partial releasers are attractive because they occupy the transporter rendering the binding site unavailable for amphetamine or any other full releaser.…”

A tropane-based ibogaine analog rescues folding-deficient SERT and DAT

“…Full substrates allow the transporter to undergo its transport cycle in a manner indistinguishable from cognate neurotransmitter. Full substrates, which differ from neurotransmitters in their cooperative interaction with the co-transported sodium, act as amphetamine-like releasers by driving the transporter into an exchange mode ( Hasenhuetl et al, 2019) Partial substrates/releasers support the transport cycle/exchange mode albeit less efficiently than full substrates/releasers, because they bind tightly to conformational intermediates and thus preclude rapid transitions (Bhat et al, 2017). Atypical inhibitors trap the transporter in conformations other than the outward facing state.…”