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-p iperazinyl)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 (pKD = 9.2) as compared to 5-HT1B, 5-HT1C, 5-HT1D, 5-HT2 and 5-HT3 sites (pKD = 6.0, 7.2, 7.5, 5.2 and 5.4, respectively). The affinity of the compound for alpha 1, alpha 2, beta 1 and beta 2 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 (pKB = 10) and displayed no intrinsic activity in this test, whereas it behaved at best as a weak antagonist on the other receptor models (pKB values < 6.9).(ABSTRACT TRUNCATED AT 250 WORDS)
Schoeffter
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P
Preclinical Research, Sandoz Pharma, Basel, Switzerland.
Fozard
J R
JR
Stoll
A
A
Siegl
H
H
Seiler
M P
MP
Hoyer
D
D
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004147:Dioxins / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D010716:Phosphatidylinositols / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*; D013141:Spiro Compounds / Q000378:metabolism / Q000494:pharmacology; D013696:Temperature; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*
D004147:Dioxins; D007211:Indoles; D010716:Phosphatidylinositols; D010879:Piperazines; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D017448:Receptors, Dopamine D2; D012702:Serotonin Antagonists; D013141:Spiro Compounds; D013844:Thiazoles; C058895:1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine; C080378:SDZ 216-525; C063249:binospirone mesylate; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000262:Adenylyl Cyclases