Glennon R A, Naiman N A, Lyon R A, Titeler M
Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0581.
J Med Chem. 1988 Oct;31(10):1968-71. doi: 10.1021/jm00118a018.
Although simple arylpiperazines are commonly considered to be moderately selective for 5-HT1B serotonin binding sites, N4-substitution of such compounds can enhance their affinity for 5-HT1A sites and/or decrease their affinity for 5-HT1B sites. A small series of 4-substituted 1-arylpiperazines was prepared in an attempt to develop agents with high affinity for 5-HT1A sites. Derivatives where the aryl portion is phenyl, 2-methoxyphenyl, or 1-naphthyl, and the 4-substituent is either a phthalimido or benzamido group at a distance of four methylene units away from the piperazine 4-position, display high affinity for these sites. One of these compounds, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (18), possesses a higher affinity than 5-HT and represents the highest affinity (Ki = 0.6 nM) agent yet reported for 5-HT1A sites.
