title: Design, synthesis, and preliminary evaluation of gabapentin-pregabalin mutual prodrugs in relieving neuropathic pain.
abstract: As a part of a program for the development of specific analgesics in relieving neuropathic pain, the purpose of the present study was to investigate a new concept that involves the conjugation of two drugs, gabapentin and pregabalin, as mutual prodrugs using a chemical modification approach. A series of gabapentin-pregabalin diester compounds were synthesized using linear or branch bis-hydroxyl linkers. Their pharmacological properties for treating neuropathic pain were investigated in a rat model of chronic sciatic nerve constriction injury (CCI). In-vivo evaluation demonstrated that 1a and 1b composed of two gabapentin molecules as well as 3a composed of gabapentin and pregabalin with the short linear linker, were effective in reversing tactile allodynia in CCI rats. Compounds with longer or side-branched linkers showed lower efficiencies and severe adverse effects.
authors.affiliation: Bejing Institute of Pharmacology and Toxicology, Bejing, China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Shi
authors.forename: He
authors.initials: H
authors.lastname: Liu
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Bohua
authors.initials: B
authors.lastname: Zhong
authors.forename: Hongju
authors.initials: H
authors.lastname: Yang
mesh_terms: D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D004195:Disease Models, Animal; D015195:Drug Design; D000077206:Gabapentin; D008297:Male; D015394:Molecular Structure; D000069583:Pregabalin; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D000588:Amines; D018712:Analgesics, Non-Narcotic; D003509:Cyclohexanecarboxylic Acids; D011355:Prodrugs; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin