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We designed the synthesis of a small library of 3-substituted-3,6-diazabicyclo[3.1.1]heptanes whose affinity on neuronal nicotinic receptors (nAChRs) was evaluated. Among the synthesized compounds, the 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-N-(2-fluorophenyl)nicotinamide 43 proved to be the most interesting compound with α4β2Ki value of 10 pM and a very high α7/α4β2 selectivity. Furthermore, compounds 35, 39 and 43 elicited a selective partial agonist activity for α4β2 nAChR subtype. Finally, in this paper we also report the conclusions on the 3,6-diazabicyclo[3.1.1]heptanes as ligands for nAChRs, resulting from our consolidated structure activity relationship (SAR) studies on this template.

The cholinergic pathways in the central nervous system (CNS) of animals and humans are important for cognitive and behavioural functions. Until a few years ago, it was thought that the key molecules transducing the cholinergic message were the metabotropic muscarinic receptors, but it is now known that ionotropic neuronal nicotinic receptors (nAChRs) are also involved. Based on recent studies, we prepared a small library of novel 3-substituted-3,6-diazabicyclo [3.1.1]heptanes, whose binding activity and functionality have been assayed. Among the synthesized compounds, the 3-(anilino)pyridine series resulted in the most interesting compounds with α4β2 Ki values ranging from 0.0225 nM (12g) to 2.06 nM (12o).

Previous studies have investigated the relevance and structure-activity relationships (SARs) of pyrazole derivatives in relation with cannabinoid receptors, and the series of tricyclic 1,4-dihydroindeno[1,2-c]pyrazoles emerged as potent CB2 receptor ligands. In the present study, novel 1,4-dihydroindeno[1,2-c]pyrazole and 1H-benzo[g]indazole carboxamides containing a cyclopropyl or a cyclohexyl substituent were designed and synthesized to evaluate the influence of these structural modifications towards CB1 and CB2 receptor affinities. Among these derivatives, compound 15 (6-cyclopropyl-1-(2,4-dichlorophenyl)-N-(adamantan-1-yl)-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide) showed the highest CB2 receptor affinity (Ki = 4 nM) and remarkable selectivity (KiCB1/KiCB2 = 2232), whereas a similar affinity, within the nM range, was seen for the fenchyl derivative (compound 10: Ki = 6 nM), for the bornyl analogue (compound 14: Ki = 38 nM) and, to a lesser extent, for the aminopiperidine derivative (compound 6: Ki = 69 nM). Compounds 10 and 14 were also highly selective for the CB2 receptor (KiCB1/KiCB2 > 1000), whereas compound 6 was relatively selective (KiCB1/KiCB2 = 27). The four compounds were also subjected to GTPγS binding analysis showing antagonist/inverse agonist properties (IC50 for compound 14 = 27 nM, for 15 = 51 nM, for 10 = 80 nM and for 6 = 294 nM), and this activity was confirmed for the three more active compounds in a CB2 receptor-specific in vitro bioassay consisting in the quantification of prostaglandin E2 release by LPS-stimulated BV2 cells, in the presence and absence of WIN55,212-2 and/or the investigated compounds. Modelling studies were also conducted with the four compounds, which conformed with the structural requirements stated for the binding of antagonist compounds to the human CB2 receptor.

The cholinergic pathways in the central nervous system (CNS) of animals and humans are important for cognitive and behavioural functions. Until a few years ago, it was thought that the key molecules transducing the cholinergic message were the metabotropic muscarinic receptors, but it is now known that ionotropic neuronal nicotinic receptors (nAChRs) are also involved. Based on recent studies, we prepared a small library of novel 3-substituted-3,6-diazabicyclo [3.1.1]heptanes, whose binding activity and functionality have been assayed. Among the synthesized compounds, the 3-(anilino)pyridine series resulted in the most interesting compounds with α

New analogues (3a-l) of the previously described α4β2 selective ligand 3-(6-halopyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptanes (2a,b) have been synthesized and their binding activity for neuronal acetylcholine receptor subtypes α4β2 and α7 were assayed. Six of these compounds (3a,b,c,j,k and l) showed high affinity and selectivity for α4β2 receptors. The phenylpyridyl-diazabicycloheptane 3c displayed Ki value of 11.17 pM for α4β2, in line with that of the halogenated homologues 3a,b, although it was characterized by an improved selectivity (Ki = 17 μM for α7 receptors). The influence of substitutions on the phenylpyridyl moiety on binding at both α4β2 and α7 receptors has been examined through the Topliss decision tree analysis. Substitution with electron-donating groups (as CH3 and OCH3) resulted in a good affinity for α4β2 receptors and substantially no affinity for α7. Amongst all the tested phenyl-substituted compounds, the p-NO2-phenyl substituted analogue 3j exhibited the highest α4β2 affinity, with Ki value comparable to that of 3c. Intrinsic α4β2 receptor mediated activity in [(3)H]-DA release assay was showed by compound 3a as well as by the reference analogue 2a, whereas phenyl substituted derivative 3c exhibited α4β2 antagonist activity.