‘Hybrid’ benzofuran–benzopyran congeners as rigid analogs of hallucinogenic phenethylamines

Abstract

Phenylalkylamines that possess conformationally rigidified furanyl moieties in place of alkoxy arene ring substituents have been shown previously to possess the highest affinities and agonist functional potencies at the serotonin 5-HT 2A receptor among this chemical class. Further, affinity declines when both furanyl rings are expanded to the larger dipyranyl ring system. The present paper reports the synthesis and pharmacological evaluation of a series of "hybrid" benzofuranyl-benzopyranyl phenylalkylamines to probe further the sizes of the binding pockets within the serotonin 5-HT 2A agonist binding site. Thus, 4(a-b), 5(a-b), and 6 were prepared as homologs of the parent compound, 8-bromo-1-(2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)-2-aminopropane 2, and their affinity, functional potency, and intrinsic activity were assessed using cells stably expressing the rat 5-HT 2A receptor. The behavioral pharmacology of these new analogs was also evaluated in the twolever drug discrimination paradigm. Although all of the hybrid isomers had similar, nanomolar range receptor affinities, those with the smaller furanyl ring at the arene 2-position (4a-b) displayed a 4-to 15-fold greater functional potency than those with the larger pyranyl ring at that position (5a-b). When the furan ring of the more potent agonist 4b was aromatized to give 6, a receptor affinity similar to the parent difuranyl compound 2 was attained, along with a functional potency equivalent to 2, 4a, and 4b. In drug discrimination experiments using rats trained to discriminate LSD from saline, 4b was more than two times more potent than 5b, the latter having a potency similar to the classic hallucinogenic amphetamine 1 (DOB).

Structure–activity relationships of serotonin 5‐HT2A agonists

“…Finally, hybrid benzofuran and benzopyran molecules were designed and tested to determine whether the 2-or 5-methoxy groups were more sterically restricted within the receptor. 86 The compound with the dihydrofuran replacing the 2-methoxy (52) had slightly higher 5-HT 2A affinity than did 53 (3.6 vs 5.3 nM, respectively); 52 also was about fourfold more potent than 53 for inducing PI turnover. In rats trained to discriminate LSD, parallel results were observed, where the 52 was about three times more potent than 53 ( Figure 22).…”

Characterization of synthetic routes to ‘Bromo‐DragonFLY’ and benzodifuranyl isopropylamine homologues utilizing ketone intermediates. Part 1: Synthesis of ketone precursors

“…[2,15] Currently BDF is only controlled under legislation in a limited number of countries worldwide. [5,6,[17][18][19][20][21] A selection of these compounds is shown in Figure 1. [16] Since the 1990s, the Nichols group has reported numerous syntheses of BDF and its analogues.…”

“…[16] Since the 1990s, the Nichols group has reported numerous syntheses of BDF and its analogues. [5,6,[17][18][19][20][21] A selection of these compounds is shown in Figure 1. However, none of these isopropylamines were prepared via a 1-aryl-2-propanone-type intermediate.…”

Iodocyclization of Diallyl-Dihydroxy Naphthalenes Using <i>N</i>-Iodosuccinimide vs Molecular Iodine in Aqueous Micelle

“…The presence of benzofurans in the heterocyclic compounds is worth mentioning and some of them are potentially bioactive and such effects include anti cancer, anti HIV and antimicrobial activities [2,[7][8][9][10][11][12][13][14][15][16].…”