Structure‐Activity Relationship Studies of CNS Agents, Part 32^[1]: Effect of Structural Modifications in 1‐Arylpiperazine Derivatives on α1‐Adrenoreceptor Affinity

Abstract

The alpha(1)-adrenergic and 5-HT1A serotonergic receptor affinities of a series of 1-arylpiperazines are presented. The role of the spacer and the influence of the terminal substituents on the alpha(1)-adrenoreceptor affinity and the 5-HT1A/alpha(1) receptor selectivity are discussed.

Arylpiperazines with Affinity Toward a1-Adrenergic Receptors

“…As an exception to this trend, compound 11 ( Fig. (1)) bearing a non-cyclic amide chain terminating with an adamantyl moiety showed good affinity, probably due to the volume and hydrophobic properties of the bulky terminal substituent [8,22]. Furthermore, an improvement of affinity was shown when the terminal fragment was fused with a phenyl ring.…”

“…This is in agreement with the accepted SARs stating that an aryl moiety is required to be linked to the piperazine ring, probably due to the conformational properties assumed by the system. In fact, it has been evidenced that an (quasi)orthogonal conformation of the piperazine ring with respect to the aryl moiety is highly profitable for the α 1 -AR affinity [8,9,33]. However, the phenylpiperazine moiety alone is not enough to show affinity toward α 1 -AR, being simple o-chloro and o-methoxyphenylpiperazines completely inactive as α 1 -AR antagonists (Table 1) [7].…”

“…The important role of hydrophobic forces in determining affinity toward α 1 -AR was evidenced in phenylpiperazines or o-methoxyphenylpiperazines bearing long aliphatic chain at the N1 nitrogen atom. In fact, while it has been established that simple phenylpiperazines are inactive as α 1 -AR antagonist [7], the presence of an octyl or hexyl chain bound to N1 led to compounds with affinity ranging from 10 to 60 nM [8] (Fig. (1), Table 1).…”

“…In fact, compounds bearing a non-cyclic amide function (such as 9 and 10 in Fig. (1)) are usually characterized by decreased affinity with respect to the corresponding derivatives where the amide/imide moiety is a part of a five-or six-membered heterocyclic ring, such as compound 12 (MM77) [8,21] in Fig. (1).…”

“…As an example, replacement of both the unsubstituted or substituted (i.e., omethoxy derivative) aromatic moiety of simple N1-n-alkyl-N4-phenylpiperazines (such as compounds 3,4,6,7 in Fig. (1)) with a 2-pyrimidine group (compounds 5,7 in Fig. (1)) markedly affect the affinity with a reduction of about two orders of magnitude [8] (Table 1). Analogous considerations could be made for more complex structures such as 14 and 15 in Fig.…”