SDZ 216-525, A SELECTIVE AND POTENT 5-HT1A RECEPTOR ANTAGONIST

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-HT1A receptor antagonist, are described in vitro (and comparisons made with those of MDL 73005 and NAN 190, two putative 5-HT1A receptor antagonists) and in vivo. In radioligand binding studies, SDZ 216-525 showed high affinity and selectivity for 5-HT1A sites (pK(D)=9.2) as compared to 5-HT1B, 5-HT1C, 5-HT1D, 5-HT2 and 5-HT3 sites (pK(D) = 6.0, 7.2, 7.5, 5.2 and 5.4, respectively). The affinity of the compound for alpha1, alpha2, beta1 and beta2 adrenoceptors, and dopamine D2 receptors was at least 50-100 times lower than for 5-HT1A sites. The effects of SDZ 216-525, MDL 73005 and NAN 190 on 5-HT1 receptor-linked second messengers were characterised in the following tests: inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus (5-HT1A), rat substantia nigra (5-HT1B) and calf substantia nigra (5-HT1D) and stimulation of inositol phosphate production in pig choroid plexus (5-HT1C). SDZ 216-525 potently antagonised the effects of 8-OH-DPAT (8-hydroxy-2-[N-dipropyl-amino]-tetralin) on 5-HT1A 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-HT1A receptors (pK(B) = 8.7), whereas MDL 73005 displayed potent and nearly full agonism at 5-HT1A receptors (pEC50 = 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 lightly reserpinised 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-HT1A receptor antagonist in vitro and in vivo.