N1-Benzenesulfonylgramine and N1-benzenesulfonylskatole: novel 5-HT6 receptor ligand templates

1-Benzenesulfonyl-5-methoxy-N,N-dimethyltryptamine (3; Ki=2.3 nM) is a 5-HT6 receptor antagonist; removal of the 5-methoxy group (i.e., 6; Ki=4.1 nM) has little impact on receptor affinity. In the present study, it is shown that the aminomethyl portion of 6 can be shortened to gramine analogue 10a (Ki=3.1 nM); a related skatole derivative 11b (Ki=12 nM) also binds with high affinity indicating that the aminoethyl portion of the tryptamines is not required for binding. Compounds 10a and 11b represent members of novel classes of 5-HT6 antagonists.