title: Synthesis and in vitro activities of NK-1 antagonists derived from L-tryptophan.
abstract: A study of structure-activity relationships of a series of L-tryptophan derivative NK-1 antagonist was performed using 3,5-bis(trifluoromethyl)benzyl ester of N-acetyl-L-Tryptophan (IV) as a starting point. The ester moiety was replaced with several amidic functions while the N-acetyl group (Ac-) was retained (compounds 1-8) or changed into a benzyloxycarbonyl group (Z-) (compounds 9-16). The compounds were tested on guinea pig ileum longitudinal muscle, rat colon muscolaris mucosae, and rat everted portal vein, representative of tachykinin NK-1, NK-2 and NK-3 receptors, respectively. Both, Ac- and Z-series showed generally moderate antagonist activity on tachykinin NK-1 receptors with respect to the reference drug IV. The most potent term was compound 2 (Ac-Trp-N(CH3)CH(CH3)Ph with S-configuration at the C-terminus) which exhibited pA2 values of 7.0, 4.2 and 4.4 on NK-1, NK-2 and NK-3 sites, respectively.
authors.affiliation: Dipartimento di Chimica Farmaceutica e Tossicologica, Università Federico II, Napoli, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Caliendo
authors.forename: F
authors.initials: F
authors.lastname: Fiorino
authors.forename: P
authors.initials: P
authors.lastname: Grieco
authors.forename: E
authors.initials: E
authors.lastname: Perissutti
authors.forename: V
authors.initials: V
authors.lastname: Santagada
authors.forename: A
authors.initials: A
authors.lastname: Calignano
authors.forename: F
authors.initials: F
authors.lastname: Mancuso
authors.forename: S
authors.initials: S
authors.lastname: Albrizio
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004386:Duodenum / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000138:chemical synthesis
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D014364:Tryptophan