In Vitro and in Vivo Neuronal Nicotinic Receptor Properties of (+)- and (−)-Pyrido[3,4]homotropane [(+)- and (−)-PHT]: (+)-PHT Is a Potent and Selective Full Agonist at α6β2 Containing Neuronal Nicotinic Acetylcholine Receptors

Abstract

Pyrido[3,4]homotropane (PHT) is a conformationally rigid, high affinity analogue of nicotine. (+)-PHT was previously shown to be 266 times more potent than (−)-PHT for inhibition of [3H]epibatidine binding to nAChRs but had no antinociceptive activity in mouse tail-flick or hot-plate tests and was not a nicotinic antagonist even when administered intrathecally. While (−)-PHT had no agonist activity, it was a potent, nicotinic antagonist in the test. Here, electrophysiological studies with rat nAChRs show (+)-PHT to be a low eficacy partial agonist selective for α4β2-nAChRs, relative to α3β4-nAChRs (15-fold) and α7-nAChRs (45-fold). (−)-PHT was an antagonist with selectivity for α3β4, relative to α4β2-(3-fold) and α7- (11-fold) nAChRs. In [3H]DA release studies in mice, (+)-PHT was 10-fold more potent than (−)-PHT at α4β2*-nAChRs and 30-fold more potent at α6β2*-nAChRs. Studies using α5KO mice suggested that much of the activity at α4β2*-nAChRs is mediated by the α4β2α5-nAChR subtype. In conditioned place preference studies, (−)-PHT was more potent than (+)-PHT in blocking nicotine reward. Off-target screens showed (+)- and (−)-PHT to be highly selective for nAChRs. The high potency, full agonism of (+)- and (−)-PHT at α6*-nAChR contrasts with the partial agonism observed for α4*-nAChR, making these ligands intriguing probes for learning more about the pharmacophores for various nAChRs.

TC299423, a Novel Agonist for Nicotinic Acetylcholine Receptors

“…Also, it is encouraging that the fold difference between the EC 50 values for α6β2 ∗ vs. α4β2 ∗ nAChRs is consistent using two distinct assays for receptor function: patch-clamp assays on identified subtypes expressed in cultured cells and [ 3 H]dopamine release assays using mouse synaptosomes (see Table 1 and Figure 3 ). A similar pattern was observed for (+)-PHT ( Carroll et al, 2015 ), but TC299423 is considerably more potent than (+)-PHT. An analog of TC299423, 2-(pyridine-3-yl)quinuclidine [see Figure 1 and ( Grady et al, 2010 )], also exhibited a similar pattern in potency among α6β2 ∗ and α4β2 ∗ nAChRs.…”

“…Our in vitro and in vivo data characterizing the properties of TC299423, along with those reported on the tropane compound, (+)-pyrido[3,4]homotropane [(+)-PHT] ( Carroll et al, 2015 ) (see Figure 1 for structure), are promising indications that selective α6β2 ∗ nAChR agonists can be identified. Given the pharmacological similarities between α6 ∗ and α4 ∗ nAChRs ( Breining et al, 2009 ), it has been challenging to identify agonists that show even modest selectivity.…”

“…The CPP data above suggest that low doses of TC299423 are weakly rewarding for WT mice but do not provide any information about the potential effects of TC299423 on the motivational properties of other substances, such as food and nicotine. Previous results show that nAChR partial agonists such as varenicline and (+)-PHT ( Figure 1 ) block nicotine-induced IVSA and CPP ( Rollema et al, 2007 ; Carroll et al, 2015 ). Thus, we tested the effects of TC299423 on male Wistar rats trained to press a lever for food pellets or intravenous nicotine infusions ( Figure 5 ).…”

Syntheses and Biological Properties of Pyrido[3,4‐b]homotropane (PHT) and its Analogues with Bridged Aza‐[n.2.1] Skeletons

“…In contrast, (−)‐PHT was found to be most potential toward α3β4‐nAChR as an antagonist and has highly potent antagonizing antinociception effects of nicotine in a tail‐flick test. Moreover, both enantiomers showed little affinity to α7‐nAChR subtype and failed to produce antinociception in two mouse acute pain models, tail‐flick and hot‐plate assays, or engender nicotine‐like responding in rat drug discrimination …”

Synthesis, Structure, and Analgesic Properties of Halogen-Substituted 4-Hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxanilides

“…It must be emphasized that in terms of modern ideas, such drugs should not cause addiction in human sand moreover, physical or psychological dependence, i.e., agonism with opioid receptors, is not acceptable in the mechanism of their analgesic action. Recently, with the purpose of searching for analgesics meeting such requirements, the agonists of neuronal nicotinic acetylcholine receptors ( n AChR) were actively studied [ 1 , 2 , 3 , 4 , 5 , 6 ]. Furthermore, they are of interest as potential agents to fight the manifestations of age-related neurodegeneration (Alzheimer’s disease [ 7 , 8 ], Parkinson’s disease [ 9 ], and various types of dementia [ 10 ]).…”