Structure−Activity Studies and Analgesic Efficacy of N-(3-Pyridinyl)-Bridged Bicyclic Diamines, Exceptionally Potent Agonists at Nicotinic Acetylcholine Receptors

Abstract

A series of exceptionally potent agonists at neuronal nicotinic acetylcholine receptors (nAChRs) has been investigated. Several N-(3-pyridinyl) derivatives of bridged bicyclic diamines exhibit double-digit-picomolar binding affinities for the alpha 4 beta 2 subtype, placing them with epibatidine among the most potent nAChR ligands described to date. Structure-activity studies have revealed that substitutions, particularly hydrophilic groups in the pyridine 5-position, differentially modulate the agonist activity at ganglionic vs central nAChR subtypes, so that improved subtype selectivity can be demonstrated in vitro. Analgesic efficacy has been achieved across a broad range of pain states, including rodent models of acute thermal nociception, persistent pain, and neuropathic allodynia. Unfortunately, the hydrophilic pyridine substituents that were shown to enhance agonist selectivity for central nAChRs in vitro tend to limit CNS penetration in vivo, so that analgesic efficacy with an improved therapeutic window was not realized with those compounds.

Chemistry and Pharmacology of a Series of Unichiral Analogues of 2-(2-Pyrrolidinyl)-1,4-benzodioxane, Prolinol Phenyl Ether, and Prolinol 3-Pyridyl Ether Designed as α4β2-Nicotinic Acetylcholine Receptor Agonists

“…34 Such a behavior resembles that of 2,5-diazabicylo[2.2.1]heptane 5-hydroxy-3-pyridyl substituted at the 2-position. 35 In summary, as shown in Table 1, the five hydroxylated compounds (R,S)-3, (S)-4, (S)-5, (S)-5a, and (S)-6 have very similar α4β2 nicotinic affinities and more or less pronounced α4β2 selectivity in binding experiments; because of hydroxylation, both the benzodioxane (R,S)-3 and the phenyl ethers (S)-4, (S)-5 and (S)-5a are upgraded to the rank of pyridyl ethers A-84543 and (S)-6, selective α4β2 ligands with nanomolar affinity, although similar interaction modes, as previously explained, cannot be postulated for the aryl ethers and the benzodioxanes. It is reasonable that the 3-hydroxyphenyl derivatives can interact better than the unsubstituted phenyl ether (S)-1 and similarly to the 3-pyridyl ether A-84543, while the 5-hydroxy-3-pyridyl ether (S)-6 behaves as a wide number of 5-substituted 3-pyridyl ethers of (S)-N-methylprolinol, 36 which generally maintain the nanomolar α4β2 affinity of A-84543.…”

Intersubunit Bridge Formation Governs Agonist Efficacy at Nicotinic Acetylcholine α4β2 Receptors

“…Increasing the size of the ring containing the charged amine beyond a certain threshold leads to increased binding affinity but decreased functional potency (31); substitution in the pyridine ring is allowed to varying degrees where 2-and 4-positions generally seem not to be tolerated, and the 5-and 6-positions seem much more accepting. In the pyridine 5-position, introduction of many different chemical functionalities is allowed, whereas substitution in the 6-position only is allowed to a limited extent (13,(31)(32)(33)(34). Common to the studies evaluating compounds from medicinal chemistry efforts is a thorough understanding of binding properties of pyridine ringsubstituted compounds.…”

“…In search of a structural explanation for the functional effects related to substituents in the pyridine 5-and 6-positions, we have investigated a series of ␣4␤2 partial agonists (1-5, Fig. 1) belonging to a thoroughly studied compound series, the 1-(pyridin-3-yl)-1,4-diazepanes (13,(31)(32)(33)(34)(35)(36). All five selected compounds bind with subnanomolar affinity to ␣4␤2 receptors (see Table 1), and they have previously been shown to possess significantly different functional profiles using fluorescent-based assays (31).…”

Identification and pharmacological characterization of 3,6-diazabicyclo[3.1.1]heptane-3-carboxamides as novel ligands for the α4β2 and α6/α3β2β3 nicotinic acetylcholine receptors (nAChRs)

“…The alkaloid epibatidine (1) has long been known as a potent ligand for a4b2 and other nAChRs with adverse effects on CNS responses, respiration, GI and cardiovascular function. Brunelle et al synthesized a series of N-(3-pyridinyl)-bridged bicyclic diamine derivatives (2) which have very high affinity for the a4b2 receptor [21]. These compounds in turn were the basis for the design of the 3,6-diazabicyclo [3.1.1] heptane skeleton (3) (Fig.…”