1,2,4-Benzothiadiazine derivatives as α1 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 α1-adrenoceptor subtypes (α1A, α1B and α1D) by functional experiments and by in vitro binding studies at human cloned 5-HT1A receptor. Compound 1 was identified as a novel α1D antagonist (pKbα1D = 7.59; α1D/α1A > 389; α1D/α1B = 135) with high selectivity over 5-HT1A receptor (5-HT1A/α1D < 0.01), while compound 6, a 3,4-dihydro-derivative, was characterized as a novel 5-HT1A receptor ligand, highly selective over α1D-adrenoceptor subtype (pKi5-HT1A = 8.04; 5-HT1A/α1D = 1096). Further pharmacological studies demonstrated that 6 is a partial agonist at 5-HT1A receptor (Emax = 23, pD2 = 6.92).