N1-Benzenesulfonylgramine and N1-Benzenesulfonylskatole: Novel 5-HT6 receptor ligand templates

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 19; pp. 3355 - 3359
• Main Authors: PULLAGURLA, Manik R, DUKAT, Malgorzata, SETOLA, Vincent, ROTH, Bryan, GLENNON, Richard A
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 06-10-2003
• Subjects: Benzene Derivatives - chemistry; Benzene Derivatives - metabolism; Biological and medical sciences; Cell Line; Humans; Ligands; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Protein Binding - physiology; Receptors, Serotonin - metabolism; Serotoninergic system; Tryptamines - chemistry; Tryptamines - metabolism; Biological fixation; Sulfonamide; Structure activity relation; Nitrogen heterocycle; Bicyclic compound; 5-HT6 serotonin receptor; Aromatic compound; Indole derivatives; Chemical synthesis; In vitro; Aromatic amine
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00612-7

1-Benzenesulfonyl-5-methoxy-N,N-dimethyltryptamine (3; K(i)=2.3 nM) is a 5-HT(6) receptor antagonist; removal of the 5-methoxy group (i.e., 6; K(i)=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 (K(i)=3.1 nM); a related skatole derivative 11b (K(i)=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-HT(6) antagonists.