N&PD Moderators: Skorpio | someguyontheinternet
Actually trypsin preferentially cleaves amide bonds where the carboxyl side of the bond is a positive Lys or Arg residue, so your compound fits. As I mentioned earlier, it would really be preferable if it gets hydrolysed in the stomach so the imine can form quickly under acid catalysis. But then that kind of defeats the whole purpose of the XR mechanism anyway.
Pretty sure the ring is necessary for binding activity.
Rings above size 7 are quite hard to make because of the entropic cost associated with their formations. There are several possible conformations that the free chain can adopt, making it less likely that the ring-forming conformation is adopted. They have no problem with enthalpy/stability though, as they have essentially no ring strain. On the contrary, for small rings it is the exact opposite - few possible conformations means ring formation is more likely, but the ring itself is highly strained making it unstable.
The ideal ring size is 5 or 6.
The strain energy actually does increase upwards from cyclohexane with cycloheptane having a similar ring strain energy to cyclopentane and the maximum being around cyclodecane or so, this is due to unfavourable eclipsed and flagpole interactions between C7 and C12-4 rings, and diminishing when the increasing ring size makes such interactions matter less and less. I'm sure the ring strain does matter as well beside long distance between two ends when they do meet and the whole to-be-the-ring structure takes a conformation close to that of the ring itself, it's probably hard to see for bigger rings as they would all typically need longer reaction times for the reaction to complete, but the strain must be the factor too, otherwise you would only need to increase reaction time to make it statistically possible for all the molecules to happen to be in the right conformation to close into a ring, right? In more complex organic compounds (I mean more complex than simple alpha-halo-omega-lithioalkane to be closed into a ring) the relationship between the ring size and the yield of a cyclization reaction is not going to be a simple one due to other steric and electronic factors, and often reaction medium as well, with reaching the energy level enough to warrant ring-formation impossible without degrading other moieties. Still, there are reactions in which bigger rings are formed in good yields under fairly mild conditions, e.g. Heck reaction and many other TM-catalyzed ones.
Anyway, that's a bit carried away.
Surely if you increase reaction time in order to try and make a large ring forming reaction to go, the reactant will just react with other molecules instead of attacking itself?
The bridge is important - if you lose it, almost all potency is lost iirc.
Not quite @aced126. This is a about twice as potent as cocaine (as DAT NET and SERT reuptake inhibitor)..!
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https://pubchem.ncbi.nlm.nih.gov/compounds/44337739#section=Top
or this even more active:
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https://pubchem.ncbi.nlm.nih.gov/compounds/44337825#section=Top
But I guess it is hard to compare since a Chlorophenyl replace the benzoate ester of cocaine and a secondary amine replacing the NMe in these cases.
This is a big finding and I'm surprised I didn't know about this. This stems a new set of DRIs - why haven't more of these been made by RC suppliers?