Synthesis and SAR of adatanserin: novel adamantyl aryl- and heteroarylpiperazines with dual serotonin 5-HT(1A) and 5-HT(2) activity as potential anxiolytic and antidepressant agents.
Several novel functionalized adamantyl aryl- and heteroarylpiperazine derivatives were prepared and examined in various receptor binding and behavioral tests to determine their serotonin receptor activities. Many compounds demonstrated modest to high affinity for 5-HT(1A) receptors, with compounds 9, 13, 23, 33, 34, and 43 being the most potent at this site. Compound 1, 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl adamantyl-1-carboxylate, demonstrated relatively high affinity for 5-HT(1A) receptors (K(i) = 8 nM) and acceptable selectivity versus D(2) receptors (K(i) = 708 mM); however, it lacked in vivo activity in serotonergic behavioral models. In contrast, compounds 9 (WY-50,324, SEB-324, adatanserin), adamantyl-1-carboxylic acid 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethylamide, and 13, adamantyl-1-carboxylic acid 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylamide, demonstrated high affinity for 5-HT(1A) binding sites (K(i) = 1 nM for both) and moderate affinity for 5-HT(2) receptors (K(i) = 73 and 75 nM, respectively). Both compounds also demonstrated partial 5-HT(1A) agonist activity in vivo in rat serotonin syndrome and 5-HT(2) antagonist activity in quipazine- and DOI-induced head shake paradigms. The selective 5-HT(1A) partial agonist and 5-HT(2) antagonist activity of 9 was accompanied by significant anxiolytic activity in an animal conflict model. On the basis of this profile, compound 9 entered development as a combined anxiolytic and antidepressant agent.
Abou-Gharbia
M A
MA
Chemical Sciences and CNS Disorders, Wyeth-Ayerst Research, CN 8000, Princeton, New Jersey 08543-8000, USA. Abougam@war.wyeth.com
Childers
W E
WE
Fletcher
H
H
McGaughey
G
G
Patel
U
U
Webb
M B
MB
Yardley
J
J
Andree
T
T
Boast
C
C
Kucharik
R J
RJ
Marquis
K
K
Morris
H
H
Scerni
R
R
Moyer
J A
JA
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000145:classification / Q000187:drug effects*; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D010879:Piperazines; D011985:Receptors, Serotonin