Thioxanthene-derived analogs as r 1 receptor ligands Richard A. Glennon, a, * Abd M. Ismaiel, a Seth Ablordeppey, b Mahmoud El-Ashmawy a and James B. Fisher c a Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, PO Box 980540, Richmond, VA 23298-0540, USA b College of Pharmacy and Pharmaceutical Science, Florida A & M University, Tallahassee, FL 32307, USA c Cambridge NeuroScience Inc., Cambridge, MA 02139, USA Received 7 January 2004; accepted 4 February 2004 Abstract—An investigation of the structure–affinity relationships for the binding of thioxanthene-related structures indicates that an intact thioxanthene ring is not required for binding at r 1 receptors, and that with the appropriate structural modifications, affinity can be enhanced to the subnanomolar level. Certain of the analogs displayed > 180-fold selectivity for r 1 versus r 2 receptors. Ó 2004 Elsevier Ltd. All rights reserved. Sigma receptors remain nearly as enigmatic today as they were immediately following their discovery more than 20years ago (reviewed 1;2 ). Sigma (r) receptors, originallythoughttorepresentatypeofopioidreceptor, are now classified as belonging to one of two major types: r 1 and r 2 receptors. 3;4 Although certain opioid receptor ligands (e.g., cyclazocine, pentazocine) bind at r 1 receptors, 1 the receptors are clearly distinct from other opioid receptors both in pharmacology and structure. Only within the past decade were r 1 receptors cloned from guinea pig liver, 5 mouse, 6 rat, 7 and human 8 sources. Sigma 1 knock-out mice also have been gener- ated to explore r receptor pharmacology. 9 Currently, r 1 ligands are being explored for their neu- roprotective actions, for example, 10 as a novel strategy against cocaine addiction and toxicity, for example, 11 and for their potential in treating various cardiovascular disorders. 12 However, one of the first therapeutic claims forsigmaligandswasaspotentialantipsychoticsbecause various antipsychotic agents were shown to possess moderatetoveryhighaffinity. 13;14 Researchonapossible role for r 1 receptors in psychotic states has not been abandoned. 15–17 Certain butyrophenones (e.g., haloperi- dol) and tricyclic antipsychotics (e.g., phenothiazines, thioxanthenes)bindat r receptorswith K i valuesranging fromabout3to500nM. 14 Wehavepreviouslyexamined haloperidol analogs 18 and have shown that they likely bind at r 1 receptors due to their close structural rela- tionship to a proposed r 1 pharmacophore. Indeed, structural modification of haloperidol analogs to more closely agree with r 1 pharmacophoric requirements re- sulted in ligands with enhanced affinity for r 1 recep- tors. 18 In other words, rather than representing a novel type of antipsychotic mechanism, r 1 receptors might simply accommodate haloperidol-like agents because they approximate the r 1 binding pharmacophore. One of the proposed pharmacophores for r 1 binding includes an amine site, flanked by two hydrophobic domains ÔAÕ and ÔBÕ. 19;20 Hydrophobic site ÔAÕ can accommodate an aryl ring and is situated about four to six atoms distant from the amine binding site; a five- atom chain is seemingly optimal. 21 A secondary hydro- phobic binding site ÔBÕ is also nearby the amine; the site is closer to the amine than site ÔAÕ and is associated with a region of bulk tolerance. 20 N-Substituted 5- (phenyl)pentylamines, for example, bind with low nanomolar affinity at r 1 receptors. 20;21 The purpose of the present investigation was to examine analogs of the thioxanthene antipsychotics to determine if they con- form to the same pharmacophoric requirements. It has been reported, for example, that cis-clopenthixol (1; IC 50 ¼ 152nM) binds at r receptors with an affinity nearly identical to that of its trans-isomer (IC 50 ¼ 145nM), 13 suggesting that the aromatic chloro group plays a minimal role in binding. Keywords: Phenylpentylamines; Antipsychotics; r Receptors. *Corresponding author. Tel.: +1-804-8288487; fax: +1-804-8287404; e-mail: glennon@hsc.vcu.edu 0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.02.018 Bioorganic & Medicinal Chemistry Letters 14 (2004) 2217–2220