Receptors have well-conserved regions that are recognized and activated by hormones and neurotransmitters. Most drugs bind to these sites and mimic or block the action of the native ligands. Using a high-throughput functional screen, we identified a potent and selective M 1 muscarinic receptor agonist from a novel structural class. Using a series of chimeric receptors, we demonstrated that this ligand activates the receptor through a region that is not conserved among receptor subtypes, explaining its unprecedented selectivity. This region of the receptor is distinct from the conserved region that is recognized by traditional ligands. The finding that receptors for small-molecule transmitters can have multiple, structurally distinct activation sites has broad implications for the study of receptor structure/function and the potential for the discovery of novel ligands with high selectivity.G-protein-coupled receptors that bind monoamine ligands (e.g., serotonin, adrenaline, dopamine, histamine, and acetylcholine) comprise the most intensively studied and exploited receptor family for the development of therapeutic agents by the pharmaceutical industry. The natural ligands for monoamine receptors are believed to bind a highly conserved pocket located deep within the transmembrane (TM)-spanning regions and to mediate receptor activation primarily through TM3, TM5, TM6, and TM7 (Spalding et al., 1994;Baldwin et al., 1997;Gether, 2000;Lu et al., 2001). Of the amino acids in these regions, 74% are identical in all five muscarinic receptor subtypes (Bonner et al., 1988). Potent small-molecule agonists are also believed to bind monoamine receptors through the same highly conserved regions (Strader et al., 1989(Strader et al., , 1991Wess et al., 1991;Page et al., 1995;Spalding et al., 1998;Ward et al., 1999;Allman et al., 2000).The muscarinic M 1 receptor has been targeted for the discovery of therapeutics for Alzheimer's Disease, and several companies have developed M 1 -selective agonists (e.g., Tecle et al., 1998;Wood et al., 1999;Bartolomeo et al., 2000;Wienrich et al., 2001). Many potent compounds came out of these programs, and several were shown to improve cognition in animals (WAY-132983 and CI-1017; Bartolomeo et al., 2000;Weiss et al., 2000) and people (Xanomeline, Bodick et al., 1997). However, many of the compounds also produced classic muscarinic side effects such as sweating, nausea and diarrhea (Bodick et al., 1997, Bartolomeo et al., 2000Thal et al., 2000). In vitro assays have shown that these compounds activate the M 1 , M 3 , M 4 , and M 5 muscarinic receptor subtypes at similar concentrations (Table 1 and Tecle Wood et al., 1999;Bartolomeo et al., 2000;Wienrich et al., 2001). This may be a direct result of the ligands activating the receptors through regions where the amino acid sequence is almost identical. Since drug interactions with nontarget receptor subtypes are often responsible for the unwanted side effects of commercial pharmaceuticals, there is strong motivation to design more selec...

The muscarinic receptor agonist activities of NDMC are unique among antipsychotics, and provide a possible molecular basis for the superior clinical effects of clozapine pharmacotherapy.

SummaryIt was demonstrated that the simplified ergot congener 8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT, is able to elicit pronounced biochemical and behavioural alterations indicative of central serotoninomimetic activity. Since these effects are resistant to prior monoamine depletion and/or synthesis inhibition by means of reserpine and a-propyldopacetamide (H22/54), respectively, they are most likely to be attributable to direct serotonin-receptor agonism by 8-OH-DPAT. With regard to central 5-HT neurotransmission the effects of 8-OH-DPAT-increased 5-HT levels, decreased 5-HIAA levels, 5-HT-synthesis rate and 5-HT utilization and inhibited 5-HT neuronal firing--are virtually identical, and comparable in potency, to those reported to result from the administration of lisuride or LSD. In contrast, however, to lisuride and LSD (included for comparative purposes in this study) as well as to several differently N-substituted, 5,6-dihydroxy, 6,7-dihydroxy and 5-,6-and 7-monohydroxy 2-aminotetralins, 8-OH-DPAT lacks appreciable effects on * Presented in part at the 19th ACNP meeting, San Juan, December 15-19,1980. [Psychoph. Bull. 17, 180-183 (1981 central catecholamine receptors. The compound may thus be regarded tho most potent, selective centrally acting 5-HT agonist described to date. accordance with this it was shown that the full-blown 5-HT-like behaviou: syndrome induced by 8-OH-DPAT cannot be antagonized by reserpir. phenoxybenzamine, propranolol and haloperidol. In addition, of the thl putative 5-HT-receptor blockers cyproheptadine, methergoline and methl thepin only the latter was able to counteract the 8-OH-DPAT-induc~ syndrome. The results are discussed in relation to the recent subclassific tion of central 5-HT receptor sites.A comparison between the chemical structures and biological activiti for different fragments of the ergot nucleus was also made. The data sugg~ that while the role of the A ring in the ergot structure for dopaminer activity at present is unclear, this ring may be important for the 5-t activity like in e.g. lisuride and LSD.Moreover, based on the present results and literature reports, it is spe, lated that a selective 5-HT-receptor agonist such as 8-OH-DPAT would i be liable to induce hallucinations in man.

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Communications to the Editor 8-Hydroxy-2-(di-n-propylamino)tetralin, a New Centrally Acting 5-Hydroxytryptamine Receptor Agonist Sir:We are currently investigating the pharmacological properties of 2-aminotetralins and related compounds using biochemical and behavioral methods recently published.1,2 It has been previously shown that 5-hydroxy-(1), 6-hydroxy-(2) and 7-hydroxy-2-(di-n-propylamino)tetralin (3) exhibit considerable dopamine (DA) receptor stimulating activity.3,4 In this series, the 5-hydroxy isomer 1 is the most active compound, being a highly active central DA-receptor agonist. Now we report the pharmacological properties of 8hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 4) which are consistent with the characterization of this compound as a central 5-hydroxytryptamine (5-HT) receptor agonist, devoid of DA-receptor stimulating activity. The DA-receptor-active 2-aminotetralins (1-3) are included for comparative purposes in this study. We are also presenting the resolution of 4 and the testing results for the enantiomers.