Sulfonamides with the N-alkyl-N 0 -dialkylguanidine moiety as 5-HT 7 receptor ligands Paweł Zajdel a, * , Gilles Subra b , Pascal Verdie b , Ewa Gabzdyl a , Andrzej J. Bojarski c , Beata Duszyn ´ ska c , Jean Martinez b , Maciej Pawłowski a a Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland b Department of Amino Acids, Peptides and Proteins, Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, University Montpellier I and II, 15 Charles Flahault, 34-093 Montpellier, France c Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Sme ˛tna Street, 31-343 Kraków, Poland article info Article history: Received 6 April 2009 Revised 6 June 2009 Accepted 10 June 2009 Available online 13 June 2009 Keywords: Serotonin Sulfonamides Guanidines Arylpiperazines Solid-phase synthesis 5-HT 1A 5-HT 7 receptor ligands abstract A series of arylsulfonamides containing guanidine incorporated in the structure of secondary amines (piperidine, piperazine) was synthesized on SynPhase Lanterns and evaluated for 5-HT 1A , 5-HT 2A , and 5-HT 7 receptors. The results demonstrated that N-alkyl-N 0 -dialkylguanidines displayed good 5-HT 7 /5- HT 1A selectivity and may be regarded as promising structural core for development of 5-HT 7 ligands. Ó 2009 Elsevier Ltd. All rights reserved. The actions of 5-hydroxytryptamine (5-HT), one of the major modulatory neurotransmitters in the central nervous system (CNS), are mediated by a number of receptors grouped in seven families. Scientific interest has focused on the most recently iden- tified 5-HT subtype—the 5-HT 7 receptor. On the basis of CNS local- ization (thalamus, hypothalamus, hippocampus, amygdala) and pre-clinical pharmacological investigation, it has been hypothe- sized that 5-HT 7 receptors may be involved in affective disorders and mood regulation connected with sleep and circadian rhythms. 1 It is also worth noting that several antipsychotic drugs exhibit a high affinity for 5-HT 7 receptors. 2 The knowledge of the involvement of 5-HT 7 receptors in the pathomechanism of psychiatric disorders has been improved by the development of selective agonists and antagonists, as well as due to the findings of several in vivo investigations. 3 Those works have proven that model 5-HT 7 antagonists (e.g., SB-269970) are efficacious in animal models of depression and anxiety. 4,5 Based, among others, on this fact, it has recently been hypothesized that 5-HT 7 antagonists seem promising in the process of elaboration of novel antidepressants with improved efficacy and devoid of a long onset of action. 6 5-HT 7 receptor antagonists, followed by many SAR studies, have been described in a few reviews. 7,8 Among this class of molecules, a variety of sulfonamide derivatives with different aliphatic and aro- matic secondary amine fragments occupy a prominent position (Fig. 1). Our interest focused on guanidine moiety since it may be regarded as one of crucial components of medicinally interesting molecules acting on CNS. 9–11 In particular it was found to be an essential part in the structure of several 5-HT receptor ligands affecting affinity and/or selectivity. 12–15 Recently, a number of derivatives containing an amidino-urea fragment have been de- scribed as 5-HT 7 ligands (Fig. 2). 16 Taking account of the above-mentioned findings, we designed a small library of compounds containing both the sulfonamide moi- ety and a guanidine motif incorporated in the secondary amine (e.g., piperidine or piperazine). Structural modifications also com- prised diversification of the length (C 2 –C 4 ) of an alkylene spacer between sulfonamide and a molecule’s basic center, and finally the kind of an arylsulfonyl fragment to determine the effect of ste- ric properties. To efficiently obtain the designed compounds, we took advantage of a solid-phase methodology and developed a ro- bust, parallel synthetic route to sulfonamide derivatives of N-alkyl- 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.06.038 * Corresponding author. Tel.: +48 12 620 54 50; fax +48 12 657 02 62. E-mail address: mfzajdel@cyf-kr.edu.pl (P. Zajdel). Bioorganic & Medicinal Chemistry Letters 19 (2009) 4827–4831 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl