Homobivalent Ligands of the Atypical Antipsychotic Clozapine: Design, Synthesis, and Pharmacological Evaluation

Abstract

To date all typical and atypical antipsychotics target the dopamine D(2) receptor. Clozapine represents the best-characterized atypical antipsychotic, although it displays only moderate (submicromolar) affinity for the dopamine D(2) receptor. Herein, we present the design, synthesis, and pharmacological evaluation of three series of homobivalent ligands of clozapine, differing in the length and nature of the spacer and the point of attachment to the pharmacophore. Attachment of the spacer at the N4' position of clozapine yielded a series of homobivalent ligands that displayed spacer-length-dependent gains in affinity and activity for the dopamine D(2) receptor. The 16 and 18 atom spacer bivalent ligands were the highlight compounds, displaying marked low nanomolar receptor binding affinity (1.41 and 1.35 nM, respectively) and functional activity (23 and 44 nM), which correspond to significant gains in affinity (75- and 79-fold) and activity (9- and 5-fold) relative to the original pharmacophore, clozapine. As such these ligands represent useful tools with which to investigate dopamine receptor dimerization and the atypical nature of clozapine.

The role of experimental and computational structural approaches in 7TM drug discovery

“…Another review presents [104] a tabulation of selected examples of GPCR drugdiscovery successes and a summary of structure-based approaches used in the identification of novel GPCR-related lead compounds. In other articles, the approaches, successes, and challenges of modeling GPCR proteins and ligands are presented [105][106][107][108][109][110].…”

Description of a Bivalent Cannabinoid Ligand with Hypophagic Properties

“…The multivalent approach to drug design has proved successful in the discovery of dimeric or hybrid drug candidates 1. Opioid 2, adrenergic 3, serotoninergic 4, and dopaminergic 5 receptors have been the most explored systems for this approach. One of the pioneer groups to synthesize bivalent opioid ligands was Portoghese's team in the early 1980s 6.…”

Novel Bivalent Ligands for D2/D3 Dopamine Receptors: Significant Cooperative Gain in D2 Affinity and Potency

“…This binding co-operativity can be reflected in increased Hill numbers (compared with unity for binding of monovalent neutral antagonists). Thus, neutral antagonist binding to D2 receptors displays Hill numbers up to 2.0 in the case of the bivalent compounds in the study of Kuhhorn et al 17 However, McRobb et al 19 report no increases in Hill numbers over unity for clozapine propylamine bivalent antagonists at D2 receptors, indicating this is a ligand-dependent phenomenon. Full monovalent agonists, recognizing high-affinity D2 states, generally display Hill numbers below unity (0.5 – 0.7) (Kuhhorn et al).…”