Novel [(diazomethyl)carbonyl]-1,2,3,4-tetrahydronaphthalene derivatives as potential photoaffinity ligands for the 5-HT1A receptor

Abstract

The photolabile (diazomethyl)carbonyl function was introduced into the 8-position of 2-(N,N-di-n-propyl-amino)-1,2,3,4-tetrahydronaphthalene in three ways, resulting in the ether 8-[[(diazomethyl)carbonyl]methoxy]-2-(N,N-di-n-propylamino)-1,2,3,4- tetrahydronaphthalene (2), the ester 8-(diazoacetoxy)-2-(N,N-di-n-propyl-amino)-1,2,3,4- tetrahydronaphthalene (3), and the ketone 8-[(diazomethyl)carbonyl]-2-(N,N-di-n-propylamino)- 1,2,3,4-tetrahydronaphthalene (4). Specific binding of these compounds at the 5-hydroxytryptamine1A sites in rat brain membranes labeled with 1 nM [3H]-8-hydroxy-2-(N,N-di-n-propylamino)- 1,2,3,4-tetrahydronaphthalene (8-OH-DPAT) showed IC50 values of ca. 75, 125, and 25 nM, respectively, for the three compounds. Photolysis of methanolic solutions of 2-4 in the absence of receptor proteins lead in each case to an abundance of Wolff-rearranged products. In the case of ether 2, subsequent beta-elimination to 8-OH-DPAT removed this compound from serious consideration as a photoaffinity ligand. Ester 3 and ketone 4 were photolysed in vitro. Whereas ester 3 was ineffective in decreasing the specific binding of [3H]-8-OH-DPAT, ketone 4 decreased 40% of the specific binding of [3H]-8-OH-DPAT in the presence (but not the absence) of ultraviolet light. Thus this ketone emerges from these studies as a good candidate for a photoaffinity label for the 5-hydroxytrypatamine1A receptor.