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ecently, we identified three types of non-mammalian gonadotropin-releasing hormone receptors (GnRHR) in the bullfrog (designated bfGnRHR-1-3), and a mammalian type-II GnRHR in green monkey cell lines (denoted gmGnRHR-2). All these receptors responded better to GnRH-II than GnRH-I, while mammalian type-I GnRHR showed greater sensitivity to GnRH-I than GnRH-II. In the present study, we designed new GnRH-II analogs and examined whether they acti- vated or inhibited non-mammalian and mammalian type-II GnRHRs. [D-Ala 6 ]GnRH-II, with D-Ala substi- tuted for Gly 6 in GnRH-II, increased inositol phos- phate (IP) production in cells stably expressing non- mammalian GnRHRs more effectively than native GnRH-II. However, it exhibited lower activity for mammalian type-I GnRHR than GnRH-I itself. Trptorelix-1, a GnRH-II antagonist, inhibited GnRH- induced IP production in cells expressing non- mammalian GnRHRs more effectively than Cetrorelix, a GnRH-I antagonist. Trptorelix-1, however, had lower potency for mammalian type-I GnRHR than Cetrorelix. Ligand-receptor binding assays revealed that [D-Ala 6 ]GnRH-II and Trptorelix-1 have higher affinities for non-mammalian GnRHRs but lower af- finities for mammalian type-I GnRHR than GnRH-II and Cetrorelix, respectively. Moreover, [D-Ala 6 ]GnRH- II and Trptorelix-1 had a higher affinity for gmGnRHR-2 than GnRH-II and Cetrorelix, respec- tively. These results indicate that [D-Ala 6 ]GnRH-II and Trptorelix-1 are highly effective agonist and antagonist, respectively, for non-mammalian and type- II mammalian GnRHRs