A series of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-
aryl-1-piperazinealkylamides was prepared and their affinity for
serotonin 5-HT7, 5-HT1A, and 5-HT2A receptors was measured using
in vitro binding assays. In relation to 5-HT7
receptor affinity,
receptor binding studies indicated that: (i) the optimal
alkyl chain length was five methylenes; (ii) an unsubstituted 1,2,3,4-tetrahydronaphthalenyl
nucleus was selected for further substitutions; and (iii) the substitution pattern of the
aryl ring linked to the
piperazine ring played a significant role. Several compound with high affinity for 5-HT7 receptors were identified. Among them, 4-(2-methoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (28), 4-(2-acetylphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (34), 4-(2-methylthiophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (44), 4-(2-hydroxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (46), 4-(2-methylphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (49) were assayed for the 5-HT7
receptor mediated relaxation of substance P-induced guinea-pig
ileum contraction. Compounds 28, 44, and 49 behaved as full agonists, compound 34 as a
partial agonist, whereas derivative 46 acted as an
antagonist.