DOPAMINE D2, D3, AND D4 RECEPTOR AFFINITIES OF 77-LH-28-1 AND ITS ANALOGUES

In functional assays, 77-LH-28-1 selectively activates M1 muscarinic acetylcholine receptor (mAChR) with respect to M2-M5 muscarinic subtypes (1). Initially classified as an allosteric agonist, 77-LH-28-1 is actually considered a bitopic agonist (2). This ligand shares a binding domain, which includes both the orthosteric binding site and a putative allosteric region, to selectively engage and activate the M1 mAChR. 77-LH-28-1 displayed antipsychotic and cognition-enhancing efficacy in pre-clinical models of schizophrenia and Alzheimer’s disease (1). Unfortunately, its efficacy was confounded by nonselective effects on other receptors (3). Among these receptors, 77-LH-28-1 has been reported to bind the short isoform of the dopamine D2 receptor (D2SR) (4). In order to know more about its pharmacological dopaminergic properties, 77-LH-28-1 was evaluated for its affinity at dopamine D2-like receptors (D2LR, D3R and D4R subtypes) by radioligand binding assays. 77-LH-28-1 showed high affinity and selectivity for D4R with respect to D2LR and D3R. To better understand the structural features required for the selective interaction with D4R, the aliphatic butyl chain of 77-LH-28-1 has been modified and the novel compounds 1-6 were prepared. These compounds and the already published compounds 7 and 8 (5) were evaluated in binding studies at dopamine D2LR, D3R and D4R.