I finally found binding affinities for cocaine. At monoamine transporter receptors:
Transporter | Cocaine affinity (nanomolar) (human!) | HDMP-28 affinity (nanomolar) | Methylphenidate affinity (nanomolar) | Ethylphenidate affinity (nanomolar) |
DAT | 230 | 33 | 131[1]/163[2] | 230 |
NET | 480 | ???? | 82[1]/206[2] | 3700 |
SERT | 740 | 76 | >10000 | >10000 |
As the chart indicates, HDMP-28 resembles cocaine in its DAT/SERT ratio, but methylphenidate analogues in general tend to have higher NET affinity than DAT affinity, whereas cocaine is the reverse. I suppose this probably helps explain why HDMP-28 has been an inferior replacement to cocaine. Ethylphenidate however shows higher DAT binding than NET binding but also has no serotonin affinity. (Note that the Ki ratio for methylphenidate from [2] is reversed from the IC50 ratio, which may indicate an artifact of data analysis. The DAT:NET inhibition ratio of both MPH and EPH is probably somewhat lower than suggested by [2].)
User reports indicate that ethylphenidate is boring and HDMP-28 is uncomfortable. It seems the pushout of the methyl->ethyl and phenyl->naphthyl morphisms would be the next step. From Davies et al it appears that adding a detoxifying 6-methoxy to naphthalene does not abolish binding, although it is hard to say about SERT affinity because it was only tried with the pyrrolidine analog of HDMP-28, which has ultra-high SERT affinity. So I await the appearance of 6'-methoxyethylnaphthidate, although the ring-unsubstituted compound is more likely to appear.
Also, based on these numbers, RR-sertraline is the most likely to be good.
Cocaine affinities from Han, D. D.; Gu, H. H.
BMC Pharmacology,
2006,
6 (1), 6.
https://doi.org/10.1186/1471-2210-6-6.
HDMP-28 affinities from Davies, H. M. L.; Hopper, D. W.; Hansen, T.; Liu, Q.; Childers, S. R. Synthesis of Methylphenidate Analogues and Their Binding Affinities at Dopamine and Serotonin Transport Sites.
Bioorganic & Medicinal Chemistry Letters, 2004,
14 (7), 1799–1802.
https://doi.org/10.1016/j.bmcl.2003.12.097.
Methylphenidate [1] and 4-fluoromethylphenidate affinites from McLaughlin, G.; Morris, N.; Kavanagh, P. V.; Power, J. D.; Dowling, G.; Twamley, B.; O’Brien, J.; Hessman, G.; Murphy, B.; Walther, D.; et al. Analytical Characterization and Pharmacological Evaluation of the New Psychoactive Substance 4-Fluoromethylphenidate (4F-MPH) and Differentiation between the (±)-Threoand (±)-Erythrodiastereomers.
Drug Testing and Analysis,
2017,
9 (3), 347–357.
https://doi.org/10.1002/dta.2167.
Methylphenidate [2] and ethylphenidate affinities from Patrick, K. S.; Corbin, T. R.; Murphy, C. E. Ethylphenidate as a Selective Dopaminergic Agonist and Methylphenidate–Ethanol Transesterification Biomarker.
Journal of Pharmaceutical Sciences,
2014,
103 (12), 3834–3842.
https://doi.org/10.1002/jps.24202.