Alpha(1)-adrenoceptor antagonists. 4. Pharmacophore-based design, synthesis, and biological evaluation of new imidazo-, benzimidazo-, and indoloarylpiperazine derivatives.
As a part of a program aimed at discovering compounds endowed with alpha(1)-adrenoceptor (AR) blocking properties, in this paper we describe the synthesis and biological characterization of the compounds designed to fully match a three-dimensional pharmacophore model for alpha(1)-AR antagonists previously developed by our research group. Accordingly, the structure of trazodone (1), identified during a database search performed by using the model as a 3D query, was chosen as the starting point for this study and modified following suggestions derived from a literature survey. In particular, the triazolopyridine moiety of trazodone was replaced with different heteroaromatic rings (such as imidazole, benzimidazole, and indole), and a pyridazin-3(2H)-one moiety was inserted into the scaffold of the new compounds to increase the overall length of the molecules and to allow for a complete fit into all the pharmacophore features. Our aim was also to study the influence of the position of both the chloro and the methoxy groups on the piperazine phenyl ring, as well as the effect of the lengthening or shortening of the polymethylene spacer linking the phenylpiperazine moiety to the terminal heterocyclic portion. Compounds obtained by such structural optimization share a 6-(imidazol-1-yl)-, 6-(benzimidazol-1-yl)-, or 6-(indol-1-yl)pyridazin-3(2H)-one as a common structural feature that represents an element of novelty in the SAR of arylpiperazine compounds acting toward alpha(1)-AR. Biological evaluation by radioligand receptor binding assays toward alpha(1)-AR, alpha(2)-AR, and 5-HT(1A) serotoninergic receptors indicated compounds characterized by very good alpha(1)-AR affinity and selectivity. Very interestingly, chemical features (such as the o-methoxyphenylpiperazinyl moiety and an alkyl spacer of three or four methylene units) that generally do not allow for 5-HT(1A)/alpha(1) selectivity led to compounds 2c and 6c with a 5-HT(1A)/alpha(1) ratio of 286 and 281, respectively. Finally, compounds with the best alpha(1)-AR affinity profile (2c, 5f, and 6c) were demonstrated to be alpha(1)-AR antagonists.
Betti
Laura
L
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa, Italy.
Botta
Maurizio
M
Corelli
Federico
F
Floridi
Monia
M
Giannaccini
Gino
G
Maccari
Laura
L
Manetti
Fabrizio
F
Strappaghetti
Giovannella
G
Tafi
Andrea
A
Corsano
Stefano
S
D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D044263:Receptors, Serotonin, 5-HT1; D013329:Structure-Activity Relationship
C464662:6-(1-benzimidazolyl)-2-((4-(2-methoxyphenyl)piperazin-1-yl)butyl)pyridazin-3(2H)-one; C464664:6-(1-indolyl)-2-((4-(2-methoxyphenyl)piperazin-1-yl)butyl)pyridazin-3(2H)-one; C464663:6-(imidazolyl)-2-((4-(2-chlorophenyl)piperazin-1-yl)heptyl)pyridazin-3(2H)-one; D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; D010879:Piperazines; D011724:Pyridazines; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1