Salvinorin A - structure/activity relationships

[specialspack]

Don't know if you have all seen this, thought it might be an interesting point of discussion.


J. Med. Chem., 48 (2), 345 -348, 2005

Studies toward the Pharmacophore of Salvinorin A, a Potent Opioid Receptor
Agonist

Thomas A. Munro, Mark A. Rizzacasa,* Bryan L. Roth, Beth A. Toth, and Feng
Yan.

Abstract:
Salvinorin A (1), from the sage Salvia divinorum, is a potent and selective
kappa opioid receptor (KOR) agonist. We screened other salvinorins and
derivatives for binding affinity and functional activity at opioid
receptors. Our results suggest that the methyl ester and furan ring are
required for activity but that the lactone and ketone functionalities are
not. Other salvinorins showed negligible binding affinity at the KOR. None
of the compounds bound to mu or delta opioid receptors.

 

[fastandbulbous]

Salvinorin A is a fuckin' big molecule, and looking at its 3D structure, it looks like a real nightmare as to where to start tinkering. Given that the furan ring and methyl ester function are required for activity (according to said paper), the logical place to start would be to produce higher homologue esters to see which produced the most potent molecule; also a similar thing with the furan ring, such as replacing it with other 5-membered heterocycles like thiophene and pyrrole.

Oth modifications, being a bit more substantial, might have to wait until they've got something akin to a total synthesis, to start playing with the alicyclic rings (got to admit, salvinorin A is way more complex compared with THC, but may have more unusual potentials). As for characterizing the kappa opiate receptor, they'll most probably have more sucess modelling from the 3,4-dichlorophenethylamide derivatives that are kappa agonists