title: On the bioactive conformation of NAN-190 (1) and MP3022 (2), 5-HT(1A) receptor antagonists.
abstract: Structural modifications of 1, a postsynaptic 5-HT(1A) receptor antagonist, provided its flexible (8, 12) and rigid (7, 9, 11, 13) analogues. Compounds 7, 8, 9, and 11 showed high 5-HT(1A) receptor affinity (K(i) = 4-72 nM). They acted as 5-HT(1A) postsynaptic receptor antagonists, since, like 1, they inhibited the behavioral syndrome, i.e., flat body posture (FBP) and forepaw treading (FT), in reserpine-pretreated rats as well as the lower lip retraction (LLR) in rats, both induced by 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), a 5-HT(1A) receptor agonist. Compound 12, which demonstrated high 5-HT(1A) receptor affinity (K(i) = 50 nM), revealed properties of a partial 5-HT(1A) receptor agonist: it induced LLR and, at the same time, inhibited FT in rats. Compound 13 (K(i) = 1600 nM) was not tested in a behavioral study. Restriction of the conformational freedom in 2, a full 5-HT(1A) receptor antagonist, yielded compound 14 with high 5-HT(1A) receptor affinity (K(i) = 47 nM) and partial agonist properties at postsynaptic 5-HT(1A) receptors in the above tests in vivo; i.e., it induced LLR and inhibited FBP and FT in rats. New constrained analogues of 1 and 2 (compounds 7 and 14, respectively) were also synthesized to recognize a bioactive conformation of those 5-HT(1A) receptor antagonists. On the basis of in vitro and in vivo investigations, binding and functional properties of compound 7 were found to reflect those of 1 at 5-HT(1A) receptors. On the other hand, compound 14, a rigid analogue of 2, showed a different activity in vivo in comparison with the parent compound. PM3 and MM calculations revealed the existence of three low-energy conformers of 7 and six of 14, all of them belonging to the extended family of conformations. The optimized structures of both analogues had a different angle between aromatic planes of terminal fragments; moreover, the heteroaromatic system of those molecules occupied various space regions. Our present study provides support to the hypothesis that the bioactive conformation of 1, responsible for its postsynaptic 5-HT(1A) receptor antagonism, is an extended linear structure represented by 7.
authors.affiliation: Departments of Medicinal Chemistry and New Drug Research, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland. paluchm@if-pan.krakow.pl
authors.forename: M H
authors.initials: MH
authors.lastname: Paluchowska
authors.forename: M J
authors.initials: MJ
authors.lastname: Mokrosz
authors.forename: A
authors.initials: A
authors.lastname: Bojarski
authors.forename: A
authors.initials: A
authors.lastname: Wesołowska
authors.forename: J
authors.initials: J
authors.lastname: Borycz
authors.forename: S
authors.initials: S
authors.lastname: Charakchieva-Minol
authors.forename: E
authors.initials: E
authors.lastname: Chojnacka-Wójcik
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D008046:Lip; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009043:Motor Activity; D010797:Phthalimides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011187:Posture; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: C402267:1-(2-methoxyphenyl)-4-(4--(2-phthalimido)cyclohexyl)piperazine; C402268:4-(3-(1-benzotriazolyl)cyclohexyl)-1-(2-methoxyphenyl)piperazine; D010797:Phthalimides; D010879:Piperazines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D014230:Triazoles; C058895:1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine; C088974:4-(3-(benzotriazol-1-yl)propyl)-1-(2-methoxyphenyl)piperazine