title: Pharmacologic characterization of the cloned human trace amine-associated receptor1 (TAAR1) and evidence for species differences with the rat TAAR1.
abstract: The hemagglutinin-tagged human trace amine-associated receptor1 (TAAR1) was stably coexpressed with rat Galpha(s) in the AV12-664 cell line, and receptor activation was measured as the stimulation of cAMP formation. After blockade of endogenously expressed alpha2- and beta-adrenoceptors with 2-[2-(2-methoxy-1,4-benzodioxanyl)]-imidazoline hydrochloride (2-methoxyidazoxan, RX821002) and alprenolol, respectively, the resulting pharmacology was consistent with that of a unique receptor subtype. beta-Phenylethylamine (beta-PEA), the putative endogenous ligand, gave an EC50 of 106 +/- 5 nM in the assay. For a series of beta-PEA analogs used to explore the pharmacophore, small substituents at ring positions 3 and/or 4 generally resulted in compounds having lower potency than beta-PEA, although several were as potent as beta-PEA. However, small substituents at ring position 2 resulted in a number of compounds having potencies as good as or better than beta-PEA. A number of nonselective antagonists known to share affinity for multiple monoaminergic receptors were evaluated for their ability to inhibit beta-PEA stimulation of the human TAAR1. None had an IC50 <10 microM. For comparison, the rat TAAR1 receptor was expressed in the AV12-664 cell line. A number of agonist compounds had significantly different relative potencies between the rat and human TAAR1, demonstrating a significant species difference between the rat and human TAAR1. The TAAR1 receptor exhibits a pharmacologic profile uniquely different from those of classic monoaminergic receptors, consistent with the structural information that places them in a distinct family of receptors. This unique pharmacologic profile suggests the potential for development of TAAR-selective agonists and antagonists to study their physiologic roles.
authors.affiliation: Eli Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Mail Drop 0510, Indianapolis, IN 46285, USA. dbwainscott@lilly.com
authors.forename: David B
authors.initials: DB
authors.lastname: Wainscott
authors.forename: Sheila P
authors.initials: SP
authors.lastname: Little
authors.forename: Tinggui
authors.initials: T
authors.lastname: Yin
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tu
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Rocco
authors.forename: John X
authors.initials: JX
authors.lastname: He
authors.forename: David L
authors.initials: DL
authors.lastname: Nelson
mesh_terms: D000818:Animals; D001483:Base Sequence; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D019329:Idazoxan / Q000031:analogs & derivatives / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008969:Molecular Sequence Data; D010627:Phenethylamines / Q000494:pharmacology; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000187:drug effects*; D013045:Species Specificity; D013329:Structure-Activity Relationship; D000095383:Trace Amine-Associated Receptors
chemical_list: D000242:Cyclic AMP; D019329:Idazoxan; D007545:Isoproterenol; D010627:Phenethylamines; D018341:Receptors, Adrenergic, alpha-2; D011943:Receptors, Adrenergic, beta; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors; C029261:phenethylamine; C058525:2-methoxyidazoxan