NOVEL BENZODIOXOPIPERAZINES ACTING AS ANTAGONISTS AT POSTSYNAPTIC 5-HT1A RECEPTORS AND AS AGONISTS AT 5-HT1A AUTORECEPTORS - A COMPARATIVE PHARMACOLOGICAL CHARACTERIZATION WITH PROPOSED 5-HT1A ANTAGONISTS

The novel benzodioxopiperazines (4-(benzodioxan-5-yl)1-[2(benzocyclobu tane-1 -yl)ethyl]piperazine} (S 14489), {4-(benzodioxan-5-yl)l -(indan -2-yl)piperazine)) (S 15535) and (4-(benzodioxan-5-yl)l -[2(indan-1-yl )ethyl]piperazine (S15931) competitively displaced the binding of [H-3 ]-8-OH-DPAT at serotonin (BHT)(1A) receptors with affinities (pK(i)s) of 9.2, 8.8 and 8.9, respectively. These values compared favorably wit h those of the structurally related eltoprazine (8.0) and the proposed 5-HT1A antagonists NAN-190 (9.2), MDL 73005 EF (8.9), SDZ 216-525 (8. 8), BMY 7378 (8.7), (-)-tertatolol (8.1), (-)-alprenolol (7.7), WAY 10 0,135(7.5) and spiperone (6.9). The affinities of S 14489, S 15535 and S 15931 for other 5-HT receptor types (5-HT1B, 5-HT1C, 5-HT1D, 5-HT2 and 5-HT3) were about 50 to 1000-fold lower. The spontaneous tail-flic ks, flat-body posture and hypothermia mediated by an action of the 5-H T1A agonist 8-OH-DPAT at postsynaptic 5-HT1A receptors were dose-depen dently and completely antagonized by S 14489, S 15535 and S15931 at do ses of 0.63 to 10.0 and 2.5 to 40.0 mg/kg for s.c. and oral administra tion, respectively. They did not induce these responses alone, and in their presence, dose-response curves for 8-OH-DPAT were shifted in par allel to the right without loss of maximal effect. By contrast, eltopr azine, MDL 73005 EF, BMY 7378 and NAN-190 behaved as ''partial'' agoni sts and only incompletely antagonized the actions of 8-OH-DPAT in thes e tests. At 5-HT1A autoreceptors, S 14489, S 15535 and S 15931 acted a s agonists in inhibiting striatal 5-hydroxytryptophan accumulation (0. 16-2.5 mg/kg, s.c.) and in abolishing the electrical activity of the d orsal raphe nucleus (0.005-0.100 mg/kg, i.v.). Eltoprazine, BMY 7378, NAN-190 and MDL 73005 EF also behaved as agonists at these 5-HT1A auto receptors, whereas WAY 100,135, spiperone, (-)-tertatolol, (-)-alpreno lol and SDZ 216-525 inhibited neither accumulation nor firing. WAY 100 ,135 and spiperone antagonized the inhibition of DRN firing induced by S 14489, S 15535 and S 15931. The affinity of 15535 for dopamine D-1 and D-2 receptors, as well as for beta-, alpha(1)- and alpha(2)-adreno ceptors, was >100-fold lower than its affinity for 5-HT1A receptors. F urther, in vivo, at doses of 10.0 to 40.0 mg/kg, s.c., it showed minim al activity in tests of dopamine D-2 (and D-1) receptor-mediated activ ity. Similarly, in vivo, S 15535 Was weakly active in a test of alpha( 1)-adrenoceptor-mediated activity. S 14489 and S 15931 also showed sub stantial selectivity vs. dopamine D-2 receptors and significant select ivity vs. alpha(1)-adrenoceptors. By contrast, marked dopamine D-2 ant agonist properties were shown by spiperone, BMY 7378 and MDL 73005 EF and pronounced alpha(1)-adrenoceptor antagonist properties by NAN-190 and SDZ 216-525. In conclusion, S 14489, S 15535 and S 15931 behave, i n vivo, as potent, competitive and orally active antagonists at postsy naptic 5-HT1A receptors and as agonists at 5-HT1A autoreceptors. These properties may confer a unique therapeutic profile and, in view of it s particular selectivity in vivo, S 15535 should prove of great utilit y as a pharmacological tool for exploration of the functional importan ce of 5-HT1A receptors.