Abstract
A new class of 5-heteroaryl-substituted 1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indoles as highly selective and potentially CNS-active alpha 1-adrenoceptor antagonists is described. The compounds are derived from the antipsychotic sertindole. The structure-affinity relationships of the 5-heteroaryl substituents, and the substituents on the piperidine nitrogen atom were optimized with respect to affinity for alpha 1 adrenoceptors and selectivity in respect to dopamine (D(1-4)) and serotonin (5-HT(1A-1B) and 5-HT(2A,2C)) receptors. The most selective compound obtained, 3-[4-[1-(4-fluorophenyl)-5-(1-methyl-1,2,4-triazol-3-yl)-1H-indol-3-yl]-1-piperidinyl]propionitrile (15c), has affinities of 0.99, 3.2, and 9.0 nM for the alpha(1a), alpha(1b), and alpha(1d) adrenoceptor subtypes, respectively, and a selectivity for adrenergic alpha(1a) receptors in respect to dopamine D2, D3, and D4 and serotonin 5-HT(2A) and 5-HT(2C) higher than 900, comparable to the selectivity of prazosin. In addition, the compound is more than 150-fold selective in respect to serotonin 5-HT(1A) and 5-HT(1B) receptors. A new basic pharmacophore for alpha 1-adrenoceptor antagonists based on a previously reported pharmacophore model for dopamine D2 antagonist is suggested.
MeSH terms
-
Adrenergic alpha-Antagonists / chemical synthesis*
-
Adrenergic alpha-Antagonists / chemistry
-
Adrenergic alpha-Antagonists / pharmacology
-
Animals
-
Antipsychotic Agents / chemical synthesis*
-
Antipsychotic Agents / chemistry
-
Antipsychotic Agents / pharmacology
-
Azoles / chemical synthesis
-
Azoles / chemistry
-
Azoles / pharmacology
-
Brain / metabolism
-
Cell Line
-
Cricetinae
-
Humans
-
Imidazoles / chemical synthesis*
-
Imidazoles / chemistry
-
Imidazoles / pharmacology
-
In Vitro Techniques
-
Indoles / chemical synthesis*
-
Indoles / chemistry
-
Indoles / pharmacology
-
Pyridines / chemical synthesis
-
Pyridines / chemistry
-
Pyridines / pharmacology
-
Pyrimidines / chemical synthesis
-
Pyrimidines / chemistry
-
Pyrimidines / pharmacology
-
Radioligand Assay
-
Rats
-
Receptors, Adrenergic, alpha-1 / drug effects*
-
Receptors, Adrenergic, alpha-1 / metabolism
-
Receptors, Dopamine / metabolism
-
Receptors, Serotonin / metabolism
-
Structure-Activity Relationship
-
Triazoles / chemical synthesis*
-
Triazoles / chemistry
-
Triazoles / pharmacology
Substances
-
3-(4-(1-(4-fluorophenyl)-5-(1-methyl-1,2,4-triazol-3-yl)-1H-indol-3-yl)-1-piperidinyl)propionitrile
-
Adrenergic alpha-Antagonists
-
Antipsychotic Agents
-
Azoles
-
Imidazoles
-
Indoles
-
Pyridines
-
Pyrimidines
-
Receptors, Adrenergic, alpha-1
-
Receptors, Dopamine
-
Receptors, Serotonin
-
Triazoles
-
sertindole