New arylpiperazine 5-HT(1A) receptor ligands containing the pyrimido[2,1-f]purine fragment: synthesis, in vitro, and in vivo pharmacological evaluation.
New 1H,3H-pyrimido[2,1-f]purine-2,4-dione derivatives of arylpiperazine (11-22) were prepared and evaluated in vitro for their affinity for 5-HT(1A), 5-HT(2A), alpha(1), and D(2) receptors. The tested compounds showed high affinity for 5-HT(1A) and alpha(1) receptors (K(i) = 1.1-87 and 10-62 nM, respectively) and moderate to low affinity for 5-HT(2A) (K(i) = 56-881 nM) and D(2) receptors (K(i) = 94-1245 nM). Compounds 14, 15, 18, 19, and 21, mostly 3'-chlorophenylpiperazine derivatives, can be classified as mixed 5-HT(1A)/5-HT(2A)/alpha(1) ligands. Compound 13, which showed the highest 5-HT(1A) receptor affinity (K(i) = 1.1 nM), was 50-fold selective in relation to alpha(1) adrenoceptors and at least 250-fold over 5-HT(2A) and D(2) sites. On the basis of in vivo functional tests, 8-phenylpiperazinoethylamino (11), 8-(2'-methoxyphenylpiperazino)ethylamino (13), and 8-phenylpiperazinopropylamino (14) derivatives of 1,3-dimethyl-1H,3H-pyrimido[2,1-f]purine-2,4-dione were identified as potent pre- and postsynaptic 5-HT(1A) receptor antagonists. 1,3-Dimethyl-7-bromo-8-(phenylpiperazinopropylamino)-1H,3H-pyrimido[2,1-f]purine-2,4-dione (20) behaved like an agonist of presynaptic and as a partial agonist of postsynaptic 5-HT(1A) receptors and resembled ipsapirone in terms of functional intrinsic activity. It revealed marked anxiolytic-like activity in the Vogel test in rats, comparable to that of the reference drug diazepam, and exhibited antidepressant-like activity in the Porsolt test in rats. The sedative effect of 20, evaluated in the open field test in rats, appeared at doses twice as high as those inducing a minimal anxiolytic-like effect and was similar to the effects of diazepam.
Jurczyk
Sławomir
S
Department of Pharmaceutical Chemistry, Collegium Medicum of the Jagiellonian University, 9 Medyczna St., 30-688 Kraków, Poland.
Kołaczkowski
Marcin
M
Maryniak
Ewa
E
Zajdel
Paweł
P
Pawłowski
Maciej
M
Tatarczyńska
Ewa
E
Kłodzińska
Aleksandra
A
Chojnacka-Wójcik
Ewa
E
Bojarski
Andrzej J
AJ
Charakchieva-Minol
Sijka
S
Duszyńska
Beata
B
Nowak
Gabriel
G
Maciag
Dorota
D
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D006993:Hypnotics and Sedatives; D008024:Ligands; D010879:Piperazines; D011687:Purines; D011743:Pyrimidines; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A