1H-Pyrazolo-[3,4-c]cyclophepta[1,2-c]thiophenes: A Unique Structural Class of Dopamine D 4 Selective Ligands Andrew Thurkauf, a Xi Chen, a Suoming Zhang, a Yang Gao, a Andrzej Kieltyka, a Jan W. F. Wasley, a Robbin Brodbeck, a William Greenlee, b Ashit Ganguly b and He Zhao a, * a Neurogen Corporation, 35 Northeast Industrial Road, Branford, CT 06405, USA b Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA Received 15 December 2002; accepted 25 April 2003 Abstract—A series of novel 1H-pyrazolo-[3,4-c]cyclophepta[1,2-c]thiophenes was prepared and screened at selected dopamine receptor subtypes. Compound 4 (NGB 4420) displayed high affinity and selectivity ( > 100-fold) for the D 4 over D 2 and other CNS receptors. This compound was identified as a D 4 antagonist via its attenuation of dopamine agonist-induced GTPg 35 S binding at D 4 receptor. # 2003 Elsevier Ltd. All rights reserved. Most classical neuroleptics are generally believed to exert their antipychotic actions through interaction with dopamine receptors and the antipsychotic efficacy of these agents has been shown to have a strong corre- lation with their affinity for the dopamine D 2 receptor subtype. The neuroleptic agent clozapine has been referred to as an atypical antipsychotic agent because it does not induce the extrapyramidal motor side effects characteristic as many other ‘typical’ antipsychotic medications such as haloperidol and chlorpromazine. A large body of research has been carried out in an effort to identify the properties of clozapine which leave it devoid of this liability. The broad spectrum of CNS receptors for which clozapine has significant affinity has made this a daunting task. 1 In 1991, Seeman characterized a new dopamine receptor subtype. This new receptor was found to be related to the D 2 receptor in that stimulation of the receptor by dopamine leads to an inhibition of c-AMP production by adenylate cyclase. 2 The localization of this new receptor subtype, termed D 4 , in the limbic areas of the central nervous system, coupled with the upregulation of this receptor found in postmortem autoradiography study of the schizophrenic brain, led to an intense effort in the following years to identify specific D 4 antago- nists. 3 The observation that clozapine, unlike typical neuroleptics, displayed a selectivity for the D 4 receptor over the D 2 sparked the theory that a selective D 4 antagonist might share its atypical neuroleptic profile. The medicinal chemistry efforts in the D 4 area lead to the identification of a wide array of chemical entities with selectivity for this receptor subtype over that of D 2 . 4 19 Although the search for D 4 selective agents has been fruitful, interest in this area was dampened by the results of a number of clinical trials, notably those of L- 745,870, CP-293,019 and U-101,387 (Fig. 1), which failed to show significant efficacy against either positive or negative symptoms of schizophrenia. 20 22 These trials bring into question the relevance of this receptor subtype in the etiology of psychosis. As part of our efforts within the area, screening of a Schering-Plough compound library for D 4 activity led to the identification of SCH 26682 (1)(Fig. 1) as a compound with significant D 4 activity. Although, in retrospect, identification of a new D 4 selective entity seems unremarkable, SCH 26682 stands out from other known D 4 selective compounds in a number of ways. In terms of basicity, the presence of piperazine, piperidine or pyrrolidine subunits lead that many D 4 selective compounds show the pK a values around 7. 23,24 In con- trast, the weakly basic pyrazole moiety of SCH 26682 0960-894X/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0960-894X(03)00587-0 Bioorganic & Medicinal Chemistry Letters 13 (2003) 2921–2924 *Corresponding author. Tel.: +1-203-488-8201x3077; fax: +1-203- 483-7027; e-mail: hzhao@nrgn.com