Synthesis and SAR of Adatanserin:  Novel Adamantyl Aryl- and Heteroarylpiperazines with Dual Serotonin 5-HT_1A and 5-HT₂ Activity as Potential Anxiolytic and Antidepressant Agents

Abstract

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.

Crystal structure of 1-(adamantan-1-yl)-3-(3-chlorophenyl)thiourea, C17H21ClN2S

“…( )* malaria infections [11], central nervous disorders [12][13][14], hyperglycaemia [15] and drug-resistant TB strain infections [16]. As a part of our current research interest in the chemotherapeutic properties of adamantane derivatives [17][18][19] and the molecular structural of adamantyl thiourea analogues [20][21][22], we report herein the synthesis and crystal title structure.…”

Crystal structure of 1-(adamantan-1-yl)-3-(4-bromophenyl)thiourea, C17H21BrN2S

“…Moreover, several adamantanebased drugs are currently employed as important medications against malaria infections [7], central nervous disorders [8][9][10], hyperglycaemia [11] and drug-resistant TB strain infections [12]. In addition, thiourea derivatives were reported to display marked antitumor [13], anti-HIV [14], antimalarial [15] and antimicrobial [16] activities.…”

Crystal structure of 3-(adamantan-1-yl)-1-(4-bromophenyl)urea, C17H21BrN2O

“…The Nbound hydrogen atoms were located on a di erence Fourier map and re ned freely. [19,20] avtivities. As a part of ongoing research project on chemotherapeutic [21,22] and structural [23,24] properties of adamantane derivatives,…”