Dihydrobenzofuran Analogues of Hallucinogens. 3. 1 Models of 4-Substituted (2,5-Dimethoxyphenyl)alkylamine Derivatives with Rigidified Methoxy Groups 2 Aaron P. Monte, ‡ Danuta Marona-Lewicka, Matthew A. Parker, David B. Wainscott, † David L. Nelson, † and David E. Nichols* Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285 Received March 11, 1996 X Tetrahydrobenzodifuran functionalities were employed as conformationally restricted bioiso- steres of the aromatic methoxy groups in prototypical hallucinogenic phenylalkylamines 1 and 2. Thus, a series of 8-substituted 1-(2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b′]difuran-4-yl)-2- aminoalkanes (7a-e) were prepared and evaluated for activity in the two-lever drug discrimination paradigm in rats trained to discriminate saline from LSD tartrate (0.08 mg/kg) and for the ability to displace [ 3 H]ketanserin from rat cortical homogenate 5-HT 2A receptors and [ 3 H]-8-OH-DPAT from rat hippocampal homogenate 5-HT 1A receptors. In addition, 1-(8- bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b′]difuran-4-yl)-2-aminopropane (7b), which was found to be extremely potent in the rat in vivo assays, was evaluated for its ability to compete with [ 125 I]DOI and [ 3 H]ketanserin binding to cells expressing cloned human 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors. All of the dihydrofuranyl compounds having a hydrophobic substituent para to the alkylamine side chain had activities in both the in vitro and in vivo assays that equaled or surpassed the activity of the analogous conformationally flexible parent compounds. For example, 7b substituted for LSD in the drug discrimination assay with an ED 50 of 61 nmol/kg and had K i values in the nanomolar to subnanomolar range for the displacement of radioligand from rat and human 5-HT 2 receptors, making it one of the most potent hallucinogen-like phenylalkylamine derivatives reported to date. The results suggest that the dihydrofuran rings in these new analogues effectively model the active binding conformations of the methoxy groups of the parent compounds 1 and 2. In addition, the results provide information about the topography and relative orientation of residues involved in agonist binding in the serotonin 5-HT 2 receptors. Introduction Representative phenylisopropylamines 1a-d and phenethylamines 2a-c remain some of the most potent and selective serotonin 5-HT 2 agonists available, having nanomolar affinity for both 5-HT 2A and 5-HT 2C receptor subtypes. 3-10 With the exception of the hallucinogenic ergolines such as d-lysergic acid N,N-diethylamide (LSD), these agents also represent some of the most potent compounds in behavioral assays for hallucinogen- like activity. 3,10-12 Because we have been interested in exploring the molecular mechanisms of action of hal- lucinogens for many years, 13,14 compounds of general structure 1 and 2 seemed logical starting points for further structure-activity relationship (SAR) studies involving a rigid analogue approach to probe the topog- raphy of the serotonin receptor agonist binding site(s). Previous SAR investigations have established that three main structural features of 1 and 2 are required for optimal in vivo and in vitro hallucinogen-like activ- ity. 13,14 These are (1) the primary amine functionality separated from the phenyl ring by two carbon atoms, (2) the presence of the 2- and 5-aromatic methoxy groups, and (3) a hydrophobic 4-substituent (alkyl, halo, alkylthio, trifluoromethyl, etc.). The presence of the methyl group R to the amine in compounds such as 1 does not enhance in vitro receptor affinity but does lend increased in vivo potency and duration of action to these molecules, possibly due to the inhibition of metabolism by deamination. We have recently suggested that the R-methyl may also increase intrinsic efficacy at the 5-HT 2A receptor. 10 Given these basic structural require- ments, rigid analogues of 1 and 2 have previously been designed to examine the pharmacological consequences of locking the various functional groups of these mol- ecules into restricted conformations. For example, the aminopropyl side chain of 1a has been incorporated into aminotetralin and aminoindan rings to restrict mobility of the alkylamine side chain, but these modifications generally lead to inactive compounds. 15 It has been proposed that serine residues are key recognition elements within the ligand binding domain of the serotonin 5-HT 2A receptor. 16 Indeed, Westkaem- per and Glennon 17 have identified specific serine resi- dues in transmembrane helices 4 and 5 of this receptor that are hypothesized to interact with the 2- and 5-methoxy groups of 1 and 2. If the heterocyclic oxygen * Author for correspondence. Phone: (317) 494-1461. Fax: (317) 494- 6790. E-mail: drdave@pharmacy.purdue.edu. † Eli Lilly and Co. ‡ Current address: Department of Chemistry, Cowley Hall, Uni- versity of Wisconsin-La Crosse, La Crosse, WI 54601. X Abstract published in Advance ACS Abstracts, June 15, 1996. 2953 J. Med. Chem. 1996, 39, 2953-2961 S0022-2623(96)00199-9 CCC: $12.00 © 1996 American Chemical Society