|Chemical and physical data|
|Molar mass||273.379 g·mol−1|
|3D model (JSmol)|
Incorporating the pyrrolidino ring onto the tetrahydroisoquinoline scaffolding markedly improves potency, although this only works for one of the available stereoisomers. JNJ-7925476 is a racemic preparation of the more potent diastereomer. Of these enantiomers, the eutomer is the (6R,10bS) stereoisomer, known as JNJ-39836966, and the distomer, (6S,10bR), is JNJ-39836732
There is some confusion over the nomenclature and cis/trans isomeric relationship at the piperidine ring. The compounds as depicted have the carbon of the pyrrolidine carbon and the phenyl cis, but Maryanoff and coworkers are of the opinion that the compound is trans. (see abstract)
The reason for this is not known because it was referred to as "cis" in earlier reports, and then later reassigned.
Ki values (nM) for JNJ-7925476 and its constituent enantiomers (JNJ-39836966 and JNJ-39836732)
In vitro, JNJ-7925476 is ~18-fold selective for the hSERT (0.9 nM) over the hNET (16.6 nM).
Ex vivo transporter occupancy of JNJ-7925476 (in rat brain) followed the ordering priority: NET > SERT > DAT.
This is consistent with the results cited earlier for rat brains (see SAR table dated 1987).
However, there is relatively poor correlation between the in vitro data presented for rats brains vs what was reported at the human transporters.
Elevations in extracellular DA in vivo was higher than expected on the basis of the in vitro transporter affinities.
The authors speculate that this could be because in the PFC where DATs are low in number, DA is predominantly transported via the NET.
- ~ 1 mg/kg of JNJ-7925476 caused concentrations of NE, 5-HT and DA to all be elevated by just under 500%, respectively.
Ex vivo occupancy of the DAT was much lower (<50%) at this dose though, whereas the NET and SERT were similar (~90%).
It took a much higher dose (c.f. 10 mg/kg) for the DAT occupancy to approach the same as the NET and SERT (i.e. saturation).
At saturation, the elevation in synaptic DA was extremely prolific (15 × baseline), whereas SER and NE was ≈ ½ this amount (i.e. 750%).
Pyrroloisoquinolines structure activity relationships
|X||Y||V||W||MA (mg/kg)||ptosis (mg/kg)||DA (nM)||NE (nM)||5-HT (nM)|
|H||H||H||H||0.34 (0.59)||0.07 (0.05)||11.3 (4.4)||0.60 (0.37)||23.5 (12.4)|
|H||H||H||OMe||no data||no data||2.8||2.2||4.5|
|SMe||H||H||H||>30 (no data)||0.30 (no data)||41.2 (23.5)||3.0 (1.8)||0.62 (0.39)|
This is a collection of all of the analogs that had favorable biological activity or an interesting substitution pattern.
All compounds are racemic preparations with the exception that brackets are for pure (+) enantiomer.
For JNJ-7925476 itself, the Ethynyl group is made from the p-iodo group (i.e. PC9951513), although no actual attempt was made by any of the authors to characterize this into the SAR list of quantitative data. Like RTI-55 it was made prepared with radiolabelled iodine is an excellent way to scan the brain using positron emission tomography.
Aloke Dutta's compound can also be made in radiolabelled form, ala Flubatine.
Instead of alkyne, one can also replace the halogen with cyanide (nitrile), ala citalopram. Although not inputted into the tablet above, this was another one of the McNeal analogues.
Ring size structure activity relationships
Expanding the ring size from pyrrolidino to piperidinyl resulted in compounds that were impotent, although contracting the ring size from 5 → 4 did not have negative repercussions on the resultant potency.
It is possible to epimerize the product to the desired RS/SR diastereomers, but the equilibrium is only 50/50.
Hence, alternative synthetic methods needed to be sought to obtain the desired isomer/s in diastereochemical excess.
If instead of an "aryl" group, a tert-butyl or a cyclohexyl was used, then it was possible to alter the stereochemical discourse of the reaction.
But the ketone cannot be reduced to an alcohol because it is part of an amide.
- Aluisio, L.; Lord, B.; Barbier, A.; Fraser, I.; Wilson, S.; Boggs, J.; Dvorak, L.; Letavic, M.; Maryanoff, B.; Carruthers, N. I.; Bonaventure, P.; Lovenberg, T. W. (2008). "In-vitro and in-vivo characterization of JNJ-7925476, a novel triple monoamine uptake inhibitor". European Journal of Pharmacology. 587 (1–3): 141–146. doi:10.1016/j.ejphar.2008.04.008. PMID 18499098.
- Maryanoff, B. E.; Mccomsey, D. F.; Castanzo, M. J.; Setler, P. E.; Gardocki, J. F.; Shank, R. P.; Schneider, C. R. (1984). "Pyrroloisoquinoline antidepressants. Potent, enantioselective inhibition of tetrabenazine-induced ptosis and neuronal uptake of norepinephrine, dopamine, and serotonin". Journal of Medicinal Chemistry. 27 (8): 943–946. doi:10.1021/jm00374a001. PMID 6747993.
- Maryanoff, B. E.; Mccomsey, D. F.; Gardocki, J. F.; Shank, R. P.; Costanzo, M. J.; Nortey, S. O.; Schneider, C. R.; Setler, P. E. (1987). "Pyrroloisoquinoline antidepressants. 2. In-depth exploration of structure-activity relationships". Journal of Medicinal Chemistry. 30 (8): 1433–1454. doi:10.1021/jm00391a028. PMID 3039136.
- Maryanoff, B. E.; Vaught, J. L.; Shank, R. P.; Mccomsey, D. F.; Costanzo, M. J.; Nortey, S. O. (1990). "Pyrroloisoquinoline antidepressants. 3. A focus on serotonin". Journal of Medicinal Chemistry. 33 (10): 2793–2797. doi:10.1021/jm00172a018. PMID 2213832.
- Morón, J. A.; Brockington; Wise; Rocha; Hope (2002). "Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines". Journal of Neuroscience. 22 (2): 389–395. PMID 11784783.
- Yaragudri, Vinod K.; Dutta, Aloke K.; Santra, Soumava; Sharma, Horrick; Voshavar, Chandrashekhar; Xu, Liping; Mabrouk, Omar; Antonio, Tamara; Reith, Maarten E. A. (2014). "Pharmacological and Behavioral Characterization of D-473, an Orally Active Triple Reuptake Inhibitor Targeting Dopamine, Serotonin and Norepinephrine Transporters". PLoS ONE. 9 (11): e113420. doi:10.1371/journal.pone.0113420. ISSN 1932-6203. PMC 4245125.
- Santra, Soumava; Gogoi, Sanjib; Gopishetty, Bhaskar; Antonio, Tamara; Zhen, Juan; Reith, Maarten E. A.; Dutta, Aloke K. (2012). "Structural Exploration of (3S,6S)-6-Benzhydryl-N-benzyltetrahydro-2H-pyran-3-amine Analogues: Identification of Potent Triple Monoamine Reuptake Inhibitors as Potential Antidepressants". ChemMedChem. 7 (12): 2093–2100. doi:10.1002/cmdc.201200352. ISSN 1860-7179.
- Santra, Soumava; Sharma, Horrick; Vedachalam, Seenuvasan; Antonio, Tamara; Reith, Maarten; Dutta, Aloke (2015). "Development of potent dopamine–norepinephrine uptake inhibitors (DNRIs) based on a (2S,4R,5R)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol molecular template". Bioorganic & Medicinal Chemistry. 23 (4): 821–828. doi:10.1016/j.bmc.2014.12.040. ISSN 0968-0896.
- Gopishetty, Bhaskar; Hazeldine, Stuart; Santra, Soumava; Johnson, Mark; Modi, Gyan; Ali, Solav; Zhen, Juan; Reith, Maarten; Dutta, Aloke (2011). "Further Structure−Activity Relationship Studies on 4-((((3S,6S)-6-Benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol: Identification of Compounds with Triple Uptake Inhibitory Activity as Potential Antidepressant Agents". Journal of Medicinal Chemistry. 54 (8): 2924–2932. doi:10.1021/jm200020a. ISSN 0022-2623.
- Maryanoff, B. (1979). "Iminium ion cyclizations. Highly stereoselective synthesis of substituted tetrahydroisoquinoline derivatives". Tetrahedron Letters. 20 (40): 3797–3800. doi:10.1016/S0040-4039(01)95527-3.
- Maryanoff, B. E.; Mccomsey, D. F.; Duhl-Emswiler, B. A. (1983). "Stereochemistry of intramolecular amidoalkylation reactions in the synthesis of polycyclic isoquinoline derivatives". The Journal of Organic Chemistry. 48 (25): 5062–5074. doi:10.1021/jo00173a053.
- Maryanoff, B. E.; Mccomsey, D. F.; Almond, H. R.; Mutter, M. S.; Bemis, G. W.; Whittle, R. R.; Olofson, R. A. (1986). "Dramatic reversal of diastereoselectivity in an N-acyliminium ion cyclization leading to hexahydropyrrolo[2,1-a]isoquinolines. A case of competing steric interactions". The Journal of Organic Chemistry. 51 (8): 1341–1346. doi:10.1021/jo00358a034.
- U.S. Patent 4,837,328
- Maryanoff, B. E.; Mccomsey, D. F.; Mutter, M. S.; Sorgi, K. L.; Maryanuff, C. A. (1988). "Highly stereocontrolled proton transfer in an enammonium-iminium rearrangement. Mechanism of the stereoselective deoxygenation of 6-aryl-6-hydroxy-1,2,3,5,6,10b-hexahydropyrrolo[2.1-]isoquinolines with borane-thf in trifluoroacetic acid". Tetrahedron Letters. 29 (40): 5073–5076. doi:10.1016/S0040-4039(00)80682-6.
- Mccomsey, D. F.; Maryanoff, B. E. (2000). "3-Aza-cope rearrangement of quaternary N-allyl enammonium salts. Stereospecific 1,3 allyl migration from nitrogen to carbon on a tricyclic template". The Journal of Organic Chemistry. 65 (16): 4938–4943. doi:10.1021/jo000363h. PMID 10956475.