Jb. Blair et al., Thieno[3,2-b]- and thieno[2,3-b]pyrrole bioisosteric analogues of the hallucinogen and serotonin agonist N,N-dimethyltryptamine, J MED CHEM, 42(6), 1999, pp. 1106-1111
The synthesis and biological activity of 6-[2-(N,N-dimethylamino)ethyl]-4H-
thienol[3,2-b]pyrrole(3a) and 4-[2-(N,N-dimethylamino)ethyl]-6H-thieno[2,3-
b]pyrrole (3b), thienopyrroles as potential bioisosteres of N,N-dimethyltry
ptamine (la), are reported. Hallucinogen-like activity was evaluated in the
two-lever drug discrimination paradigm using LSD- and DOI-trained rats. Ne
ither 3a nor 3b substituted for LSD or DOI up to doses of 50 mu mol/kg. By
comparison, la fully substituted in LSD-trained rats. However, 3a and 3b fu
lly substituted for the 5-HT1A agonist LY293284 ((-)-(4R)-6-acetyl-4-(di-n-
propylamino)-1,3,4,5-tetrahydrobenz[c,d]indole). Both 3a and 3b induced a b
rief "serotonin syndrome" and salivation, an indication of 5-HT1A receptor
activation. At the cloned human 5-HT2A receptor 3b had about twice the affi
nity of 3a. At the cloned human 5-HT2B and 5-HT2C receptors, however, 3a ha
d about twice the affinity of 3b. Therefore, thiophene lacks equivalence as
a replacement for the phenyl ring in the indole nucleus of tryptamines tha
t bind to 5-HT2 receptor subtypes and possess LSD-like behavioral effects.
Whereas both of the thienopyrroles had lower affinity than the correspondin
g la at 5-HT2 receptors, 3a and 3b had significantly greater affinity than
la at the 5-HT1A receptor. Thus, thienopyrrole does appear to serve as a po
tent bioisostere for the indole nucleus in compounds that bind to the serot
onin 5-HT1A receptor. These differences in biological activity suggest that
serotonin receptor isoforms are very sensitive to subtle changes in the el
ectronic character of the aromatic systems of indole compounds.