1,2,4-Benzothiadiazine derivatives as alpha1 and 5-HT1A receptor ligands.
A series of new 1,2,4-benzothiadiazine derivatives with an arylpiperazine mojety linked at position 3 of the heterocyclic ring were synthesized and assessed for their pharmacological profiles at alpha(1)-adrenoceptor subtypes (alpha(1A), alpha(1B) and alpha(1D)) by functional experiments and by in vitro binding studies at human cloned 5-HT(1A) receptor. Compound 1 was identified as a novel alpha(1D) antagonist (pK(b)alpha(1D)=7.59; alpha(1D)/alpha(1A)>389; alpha(1D)/alpha(1B)=135) with high selectivity over 5-HT(1A) receptor (5-HT(1A)/alpha(1D)<0.01), while compound 6, a 3,4-dihydro-derivative, was characterized as a novel 5-HT(1A) receptor ligand, highly selective over alpha(1D)-adrenoceptor subtype (pK(i)5-HT(1A)=8.04; 5-HT(1A)/alpha(1D)=1096). Further pharmacological studies demonstrated that 6 is a partial agonist at 5-HT(1A) receptor (E(max)=23, pD(2)=6.92).
Tait
Annalisa
A
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy. tait.annalisa@unimore.it
Luppi
Amedeo
A
Franchini
Silvia
S
Preziosi
Elisa
E
Parenti
Carlo
C
Buccioni
Michela
M
Marucci
Gabriella
G
Leonardi
Amedeo
A
Poggesi
Elena
E
Brasili
Livio
L
D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D013154:Spleen; D013329:Structure-Activity Relationship; D014649:Vas Deferens
D058668:Adrenergic alpha-1 Receptor Antagonists; D001581:Benzothiadiazines; D008024:Ligands; D018340:Receptors, Adrenergic, alpha-1; D058825:Serotonin 5-HT1 Receptor Agonists; D016244:Guanosine 5'-O-(3-Thiotriphosphate)