Abstract
A series of 1,3-dioxolane-based compounds incorporating a lactam (2-4) or imide (5-7) moiety was synthesized and the pharmacological profile at alpha(1)-adrenoceptor subtypes and 5-HT(1A) receptor was assessed through binding and functional experiments. Starting from the 2,2-diphenyl-1,3-dioxolane derivative 1, previously shown to be a selective alpha(1a(A))/alpha(1d(D))-adrenoceptor subtype antagonist, over alpha(1b(B)) subtype and 5-HT(1A) receptor, and replacing one phenyl ring with lactam or imide moiety a reduction of alpha(1)/5-HT(1A) selectivity is observed, mainly due to the increase in 5-HT(1A) affinity. In functional experiments lactam derivatives seems to favour 5-HT(1A) receptor antagonism (pKb = 7.20-7.80) and alpha(1B)-adrenoceptor antagonist selectivity (alpha(1B)/alpha(1A) and alpha(1B)/alpha(1D) of about 10-fold). The most interesting of the various imide derivatives is compound 7t, which is a selective alpha(1D)-adrenoceptor antagonist (pKb = 8.1 and alpha(1D)/alpha(1A) and alpha(1D)/alpha(1B) selectivity ratios of 16 and 11 respectively) whereas at 5-HT(1A) receptor it is a potent partial agonist (pD2 = 7.98, E(max) = 60%).]. Given that cis and trans diastereomer pairs for 2-7 are possible, a computational strategy based on molecular docking studies was used to elucidate the atomic details of the 5HT(1A)/agonist and 5HT(1A)/antagonist interaction.
2010 Elsevier Masson SAS. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adrenergic alpha-1 Receptor Agonists / chemical synthesis
-
Adrenergic alpha-1 Receptor Agonists / chemistry
-
Adrenergic alpha-1 Receptor Agonists / metabolism
-
Adrenergic alpha-1 Receptor Agonists / pharmacology
-
Adrenergic alpha-1 Receptor Antagonists / chemical synthesis
-
Adrenergic alpha-1 Receptor Antagonists / chemistry
-
Adrenergic alpha-1 Receptor Antagonists / metabolism
-
Adrenergic alpha-1 Receptor Antagonists / pharmacology
-
Animals
-
Dioxolanes / chemical synthesis
-
Dioxolanes / chemistry*
-
Dioxolanes / metabolism*
-
Dioxolanes / pharmacology
-
Humans
-
Imides / chemistry*
-
Lactams / chemistry*
-
Ligands
-
Male
-
Models, Molecular
-
Protein Binding
-
Protein Conformation
-
Rats
-
Receptor, Serotonin, 5-HT1A / chemistry
-
Receptor, Serotonin, 5-HT1A / metabolism*
-
Receptors, Adrenergic, alpha-1 / chemistry
-
Receptors, Adrenergic, alpha-1 / metabolism*
-
Serotonin 5-HT1 Receptor Agonists / chemical synthesis
-
Serotonin 5-HT1 Receptor Agonists / chemistry
-
Serotonin 5-HT1 Receptor Agonists / metabolism
-
Serotonin 5-HT1 Receptor Agonists / pharmacology
-
Serotonin 5-HT1 Receptor Antagonists / chemical synthesis
-
Serotonin 5-HT1 Receptor Antagonists / chemistry
-
Serotonin 5-HT1 Receptor Antagonists / metabolism
-
Serotonin 5-HT1 Receptor Antagonists / pharmacology
-
Stereoisomerism
-
Structure-Activity Relationship
-
Substrate Specificity
Substances
-
Adrenergic alpha-1 Receptor Agonists
-
Adrenergic alpha-1 Receptor Antagonists
-
Dioxolanes
-
Imides
-
Lactams
-
Ligands
-
Receptors, Adrenergic, alpha-1
-
Serotonin 5-HT1 Receptor Agonists
-
Serotonin 5-HT1 Receptor Antagonists
-
Receptor, Serotonin, 5-HT1A
-
formal glycol