Synthesis and structure-activity relationships of a new model of arylpiperazines. 4. 1-[omega-(4-arylpiperazin-1-yl)alkyl]-3-(diphenylmethylene)-2,5-pyrrolidinediones and -3-(9H-fluoren-9-ylidene)-2,5-pyrrolidinediones: Study of the steric requirements of the terminal amide fragment on 5-HT1A affinity/selectivity

In the present paper, we report the synthesis and the binding profile on 5- HT1A, alpha(1) and D-2 receptors of a new series of 1-[omega-(4-arylpiperaz in-1-yl)alkyl]-3-(diphenylmethylene)-2,5-pyrrolidinediones (III) (1-4) and -3-(9H-fluoren-9-ylidene)-2,5-pyrrolidinediones (IV) (1-4), in which the al kyl linker contains 1-4 methylenes and the aryl group is variously substitu ted. The results obtained are compared to those previously reported for bic yclohydantoin (I) and the related bicyclic amine (II) series. A considerabl e part of the tested compounds 1-4 demonstrated moderate to high affinity f or 5-HT1A and alpha(1) receptor binding sites but had no affinity for D-2 r eceptors. The study of the length of the alkyl chain and the imide substruc ture has allowed us to suggest some differences between the 5-HT1A and the alpha(1)-adrenergic receptors: (i) for III and IV, affinity for the 5-HT1A receptor as a function of the length of the methylene linker decreases in t he order 4 > 1 >> 3 similar to 2, while for the alpha(1) receptor affinity decreases in the order 3 similar to 4 similar to 1 similar to 2; (ii) the n o-pharmacophoric steric pocket (receptor zone which does not hold the pharm acophore of the ligand but holds a nonessential fragment of the molecule) i n the 5-HT1A receptor has less restriction than the corresponding pocket in the alpha(1) receptor. Compounds 3a,e, which are highly selective for al-a drenergic receptors, displayed antagonist activity. On the other hand, the best compromise between affinity and selectivity for 5-HT1A receptors is re ached in these new series with n = 1, which is in agreement with our previo us results for the bicyclohydantoin derivatives I. Two selected compounds ( 1d and 4e) retain agonist properties at postsynaptic 5-HT1A receptors. The same 5-HT1A agonist profile found in these compounds suggests the existence of two different no-pharmacophoric steric pockets in this receptor and a d ifferent interaction of compounds with n = 1 and it = 4. The information ob tained from the interpretation of the energy minimization and 2D-NOESY expe riments of compounds 1-4 together with the synthesis and binding data of ne w conformationally restrained analogues 4k-m is in good agreement with this working hypothesis.