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Nichol's benzofuran-pyran compounds: fly homologues

nuke

nuke

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'Hybrid' benzofuran-benzopyran congeners as rigid analogs of hallucinogenic phenethylamines.
Schultz DM, Prescher JA, Kidd S, Marona-Lewicka D, Nichols DE, Monte A.

Department of Chemistry, University of Wisconsin-La Crosse, 1725 State Street, La Crosse, WI 54601, USA.

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 two-lever 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, with the latter having a potency similar to the classic hallucinogenic amphetamine 1 (DOB).
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Not really new but I couldn't find another thread about it. What are the structures of these compounds? What comformation at the 2-position is most idea for activity?

http://www.ncbi.nlm.nih.gov/pubmed/18467103
 
I thought they were this 2-(9-bromo-8H-furo[2,3-g]chromen-4-yl)ethanamine, but that doesn't look right. I can't figure out if the pyran is oriented properly or not.
 
Is this something like this?

bromopyro.png
 
The interesting thing about these partial pyran compounds is that they cause mice to select the lever for LSD on a reliable basis with doses similar to dragonflies however they have barely any behavioural disruption as compared to the dragonflies. The psychopharmacy of the compounds might resemble something extremely 'clean' (confusionless?) with similar potencies to 2c-b-fly, however we won't know until some daring human attempts to consume them.
 
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