Wilkins Lincoln H, Miller Dennis K, Ayers Joshua T, Crooks Peter A, Dwoskin Linda P
College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
AAPS J. 2006 Jan 13;7(4):E922-30. doi: 10.1208/aapsj070490.
Pyridine N-n-alkylation of S(-)-nicotine (NIC) affords N-n-alkylnicotinium analogs, previously shown to competitively inhibit [(3)H]NIC binding and interact with alpha4beta2* nicotinic receptors (nAChRs). The present study determined the ability of the analogs to inhibit NIC-evoked (86)Rb(+) efflux from rat thalamic synaptosomes to assess functional interaction with alpha4beta2* nAChRs. In a concentration-dependent manner, NIC evoked (86)Rb(+) efflux (EC(50) = 170 nmol/L). Analog-induced inhibition of NIC-evoked (86)Rb(+) efflux varied over a approximately 450-fold range. Analogs with long n-alkyl chain lengths (C(9)-C(12)) inhibited efflux in the low nmol/L range (IC(50) = 9-20 nmol/L), similar to dihydro-beta-erythroidine (IC(50) = 19 nmol/L). Compounds with shorter n-alkyl chain lengths (C(1)-C(8)) produced inhibition in the low micromol/L range (IC(50) = 3-12 micromol/L). C(10) and C(12) analogs completely inhibited NIC-evoked efflux, whereas C(1-9) analogs produced maximal inhibition of only 10% to 60%. While the C(10) analog N-n-decylnicotinium iodide (NDNI) did not produce significant inhibition of NIC-evoked dopamine release in previously reported studies, NDNI possesses high affinity for [(3)H]NIC binding sites (K(i) = 90 nmol/L) and is a potent and efficacious inhibitor of NIC-evoked (86)Rb(+) efflux as demonstrated in the current studies. Thus, NDNI is a competitive, selective antagonist at alpha4beta2* nAChRs.
对S(-)-尼古丁（NIC）进行吡啶N-正烷基化反应可得到N-正烷基烟碱类似物，此前的研究表明这些类似物能竞争性抑制[(3)H]NIC结合，并与α4β2烟碱型受体（nAChRs）相互作用。本研究测定了这些类似物抑制NIC诱发的大鼠丘脑突触体(86)Rb(+)外流的能力，以评估其与α4β2 nAChRs的功能相互作用。NIC以浓度依赖的方式诱发(86)Rb(+)外流（EC(50)=170 nmol/L）。类似物对NIC诱发的(86)Rb(+)外流的抑制作用在约450倍的范围内变化。具有长正烷基链长度（C(9)-C(12)）的类似物在低nmol/L范围内抑制外流（IC(50)=9-20 nmol/L），与二氢-β-刺桐碱（IC(50)=19 nmol/L）相似。具有较短正烷基链长度（C(1)-C(8)）的化合物在低微摩尔/升范围内产生抑制作用（IC(50)=3-12 μmol/L）。C(10)和C(12)类似物完全抑制NIC诱发的外流，而C(1-9)类似物产生的最大抑制仅为10%至60%。虽然在先前报道的研究中，C(10)类似物N-正癸基碘化烟碱（NDNI）对NIC诱发的多巴胺释放没有产生显著抑制作用，但NDNI对[(3)H]NIC结合位点具有高亲和力（K(i)=90 nmol/L），并且如本研究所示，是NIC诱发的(86)Rb(+)外流的有效抑制剂。因此，NDNI是α4β2* nAChRs的竞争性、选择性拮抗剂。
