Synthesis and structure-affinity relationship investigations of 5-heteroaryl-substituted analogues of the antipsychotic sertindole. A new class of highly selective alpha(1) adrenoceptor antagonists.
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.
Balle
Thomas
T
Medicinal Chemistry Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark.
Perregaard
Jens
J
Ramirez
Martha Teresa
MT
Larsen
Anna Kirstine
AK
Søby
Karina Krøjer
KK
Liljefors
Tommy
T
Andersen
Kim
K
D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C470757:3-(4-(1-(4-fluorophenyl)-5-(1-methyl-1,2,4-triazol-3-yl)-1H-indol-3-yl)-1-piperidinyl)propionitrile; D000317:Adrenergic alpha-Antagonists; D014150:Antipsychotic Agents; D001393:Azoles; D007093:Imidazoles; D007211:Indoles; D011725:Pyridines; D011743:Pyrimidines; D018340:Receptors, Adrenergic, alpha-1; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D014230:Triazoles; C066304:sertindole