Synthesis and 5-HT1A/5-HT2A activity of some butyl analogs in the group of phenylpiperazine alkyl pyrimido[2,1-f]theophyllines.

New arylpiperazines with a four-methylene spacer containing a terminal pyrimido[2,1-f] theophylline fragment were synthesized, and their 5-HT1A and 5-HT2A receptor affinities were determined. All these compounds displayed a high affinity for 5-HT1A receptors (Ki=0.5-21.5 nM), and low affinity for 5-HT2A ones. The results of in vivo experiments showed that compounds revealed potential agonistic activity at presynaptic 5-HT1A receptors, whereas their functional activity at postsynaptic 5-HT1A sites was diversified. In fact, compounds and behaved like partial agonists, antagonists or agonists of postsynaptic 5-HT1A receptors, respectively. The pharmacological properties of the tested compounds were discussed in comparison with those of the three methylene-analogs described earlier.