There has been much evidence in recent years to suggest that the kappa opioid receptor plays a significant role in mediating a number of behavioural disorders including drug abuse and depression. Previous in vitro evaluation within the group of secondary and tertiary amines derived from 2-amino-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-7-ol has suggested that all behave as pure opioid antagonists. These findings prompted further synthetic and pharmacological investigations of this scaffold, with the eventual aim of developing a short-acting selective kappa opioid antagonist to further probe the receptor.

The ability of derivatives of 2-aminotetralins (2AT), cis- or trans-isomers of octahydrobenzo[f]quinolines (BfQ) and clonidine to modulate acetylcholine release was studied using field-stimulated guinea pig ilea (GPI). Antihistaminic and antiacetylcholine activities were also determined using isolated superfused segments of GPI. Hydroxylated 2AT, BfQ and clonidine inhibited field stimulation-induced contractions through α-adrenoceptor mechanisms which were antagonized by phentolamine. In contrast, the inhibition produced by nonhydroxylated 2AT was not attenuated by α-adrenoceptor antagonism. 2AT, trans-7,8-dihydro-BfQ and cis-8,9-dihydroxy-BfQ inhibited contractions induced by nicotine bitartrate using superfused GPI. Clonidine was inactive as an antinicotinic agent and there was no correlation between a compound's ability to inhibit contractions induced by field stimulation and its antinicotinic activity. Various 2AT derivatives demonstrated weak antimuscarinic and/or antihistaminic activities on superfused ileal segments. These data demonstrate that these agents posses a spectrum of pharmacological activity.

The interactions of 5,6- and 6,7-dihydroxy derivatives of 2-aminotetralin with [3H]clonidine and [3H]clonidine and [3H]prazosin as well as with [3H]spiperone binding sites in rat cerebral cortex membrane preparations were investigated. The hydroxy derivatives of 2-aminotetralin tested showed significant interaction with [3H]clonidine as well as with [3H]spiperone binding sites while for [3H]prazosin binding site these agents appeared virtually inactive. For interaction with [3H]clonidine binding site 6,7-dihydroxy substitutions impart greater potency that 5,6-dihydroxy substitutions and N-alkyl substitutions either make no difference or reduce the affinity of these compounds. N-alkyl substitutions, however, markedly enhance the affinity of 5,6-dihydroxy derivatives for interactions with [3H]spiperone binding site. The results suggest that some hydroxy derivatives of aminotetralin have significant interaction with both central α2-adrenoceptor and D2-dopamine receptor systems.

A series of aminotetralones and aminotetralins were synthesized from the common intermediate F, 3-amino-2,2-dimethyl-7-methoxy- 1-tetralone. The final compounds derived from F were simple substituted and/or reduced analogues. The products would allow a progressive structure activity relationship to be drawn based on pharmacological testing. The common intermediate F was synthesized utilizing a six step procedure starting with p-methoxyphenylacetic acid. The overall yield from the precursor to the F:HC1 was 25%. Compound F was either O-demethylated to form 3-amino-2,2-dimethyl-7-hydroxy-l-tetralone (I) or was dimethylated on the amine and subsequently O-demethylated to yield the 3-dimethylamino-7-hydroxy-2,2-dimethyl-l-tetralone (J). The last major modification was the reduction of the carbonyl group in J to a methylene, to produce the 3-dimethylamino-7-hydroxy-2,2-dimethyltetralin (L). These final compounds I, J, and L, as well as the intermediates leading to them (compounds F, II, G, and K), were tested for opioid activity in the isolated guinea pig ileum assay as described by Kosterlitz. All of the compounds exhibited agonist activity. They generally fell into three groups. Compound J was the most potent, giving 1/40 the potency of normorphine (NM). The majority of compounds (F, H, K, and L) were of intermediate potency, ranging in activity from 1/500 to 1/700 the potency of NM. The last two compounds I and G were not only the least potent at 1/2000 to 1/5000 that of NM, but also the least efficacious. In evaluation of the receptor selectivity of the compounds synthesized, a range of selectivity was observed. Compound J was the only compound which appeared to exhibit 100% of its activity through the mu receptor. The other compounds had varying degrees of mixed receptor agonism.