SDZ 216–525, a selective and potent 5-HT 1A receptor antagonist

Abstract

The pharmacological properties of SDZ 216–525, methyl 4-{4-[4(1,1,3-trioxo-2H,1,2-benzoisothiazol-2-yl)butyl]-1-piperazinyl}1H-indole-2-carboxylate, a new selective and potent 5-HT 1A receptor antagonist, are described in vitro (and comparisons made with those of MDL 73005 and NAN 190, two putative for 5-HT 1A receptor antagonists) and in vivo. In radioligand binding studies, SDZ 216–525 showed high affinity and selectivity for 5-HT 1A sites (pK D = 9.2) as compared to 5-HT 1B, 5-HT 1C, 5-HT 1D, 5-HT 2 and 5-HT 3 sites (pK D= 6.0, 7.2, 7.5, 5.2 and 5.4, respectively). The affinity of the compound for α 1, α 2, β 2 and β 2 adrenoceptors. and dopamine D 2 receptors was at least 50–100 times lower than for 5-HT 1A sites. The effects of SDZ 216–525, MDL 73005 and NAN 190 on 5-HT 1 receptor-linked second messengers were characterized in the following tests: inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus (5-HT 1A), rat substantia nigra (5-HT 1B) and calf substantia nigra (5-HT 1D) and stimulation of inositol phosphate production in pig choroid plexus (5-HT 1C). SDZ 216–525 potently antagonised the effects of 8-OH-DPAT (8-hydroxy-2[N-diprophyl-amino]-tetralin) on 5-HT 1A receptors (pK B = 10) and displayed no intrinsic activity in this test, whereas it behaved at best as a weak antagonist on the other receptor models pK B values < 6.9). NAN 190 also behaved as a potent antagonist at 5-HT 1A receptors (pK B = 8.7), whereas MDL 73005 displayed potent and nearly full agonism at 5-HT 1A receptors (pEC 50 = 7.3, E max = 92%). Both compounds behaved broadly similarly to SDZ 216–525 in the other models. In vivo, SDZ 216–525 did not induce forepaw treading or flat body posture in lighlty44 reserpinies rats at up to 1 mg/kg s.c., whereas the behavioural responses to a submaximal dose of 8-OH-DPAT (0.25 mg/kg s.c.) were inhibited dose dependently by SDZ 216–525 over the range 0.03−1 mg/kg s.c. Similarly, SDZ 216–525 over the same dose range suppressed dose dependently the hypothermic effects of 8-OH-DPAT. These data demonstrate SDZ 216–525 to be a potent and selective 5-HT 1A receptor antagonist in vitro and in vivo.